key: cord- -jfawhnsq authors: caron, alexandre; cappelle, julien; cumming, graeme s; de garine-wichatitsky, michel; gaidet, nicolas title: bridge hosts, a missing link for disease ecology in multi-host systems date: - - journal: vet res doi: . /s - - - sha: doc_id: cord_uid: jfawhnsq in ecology, the grouping of species into functional groups has played a valuable role in simplifying ecological complexity. in epidemiology, further clarifications of epidemiological functions are needed: while host roles may be defined, they are often used loosely, partly because of a lack of clarity on the relationships between a host’s function and its epidemiological role. here we focus on the definition of bridge hosts and their epidemiological consequences. bridge hosts provide a link through which pathogens can be transmitted from maintenance host populations or communities to receptive populations that people want to protect (i.e., target hosts). a bridge host should ( ) be competent for the pathogen or able to mechanically transmit it; and ( ) come into direct contact or share habitat with both maintenance and target populations. demonstration of bridging requires an operational framework that integrates ecological and epidemiological approaches. we illustrate this framework using the example of the transmission of avian influenza viruses across wild bird/poultry interfaces in africa and discuss a range of other examples that demonstrate the usefulness of our definition for other multi-host systems. bridge hosts can be particularly important for understanding and managing infectious disease dynamics in multi-host systems at wildlife/domestic/human interfaces, including emerging infections. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. ecological functional approaches classify organisms according to what they do, and/or what they eat. they offer an alternative perspective to taxonomic classifications for identifying trends within and making sense of ecological complexity. applications of functional group concepts, which date back to fundamental ideas about biomass distributions across different trophic levels [ ] , have been crucial in advancing ecological understanding. more recently, ecological functional analyses have achieved prominence as a way of linking taxonomic survey data and the provision of ecosystem services [ ] . functional analyses thus remain an important research area in ecology. in epidemiology, functional concepts have clear potential utility but are still in a relatively early stage of development. classical epidemiology relies heavily on single-species studies, particularly those of people (e.g., analyses of measles and smallpox in human populations [ ] ). in contemporary epidemiological studies, in the last fifteen years, under the influence of ecology, the scope of epidemiology is being broadened to include plant and animal communities in which multiple different species can contribute to the maintenance and spread of pathogens in host populations [ ] . in multihost systems, the role played by each host population in pathogen dynamics is determined by the species' competence for the pathogen (i.e., its receptivity to infection and its capacity to replicate and transmit the pathogen [ ] ), its exposure to the pathogen determined by the host ecology/behaviour and its interactions with other host populations (including vectors for vectorborne infections) leading to infectious contacts, and finally, the composition of the host community that will determine the range of inter-host interactions [ ] . one of the central questions in disease ecology is that of how the community composition of potential host species relates to the dynamics of pathogen transmission within the host community, as opposed to within a population of a single species. the complexity of this problem can be simplified by assigning epidemiological functions to relevant traits that define an organism's role in the epidemiology of a given pathogen. for example, animals that undertake long movements (a trait) may contribute to the epidemiological function (pathogen disperser) of spreading pathogens over large distances (a role). grouping organisms by epidemiological functions facilitates the development of eco-epidemiological models for a given pathogen in relation to an entire animal community [ ] . this approach could potentially play an important role in guiding research, as well as in the surveillance and control of animal and zoonotic diseases [ ] . although some progress has been made in the characterization of epidemiological functional groups, (e.g., clear definition of the maintenance function [ , ] ), other epidemiological functions remain incompletely defined, especially those relating to the transmission of pathogens between groups of hosts. in this paper we first define the transmission function in relation to the maintenance function. we then focus on the concept of "bridge hosts" and demonstrate their potential importance in the ecology of disease transmission in multi-host systems. though closely related concepts have been used previously [ ] [ ] [ ] , we believe that a refined definition embedded in a clear functional framework is still lacking. lastly, we present an operational framework to identify potential bridge host populations, using as a case study the ecology of avian influenza viruses at the wild/domestic bird interface in africa and also giving other multi-host systems examples. we use "host" to refer to a host population, a host species, or a host community. the smallest epidemiological unit to which we will refer is a host population, acknowledging the fact that individual variability can also substantially impact pathogen transmission (e.g. "superspreader", [ ] ). as defined by haydon et al. [ ] and more recently revised by viana et al. [ ] , a conceptual framework for the role of hosts in epidemiology requires the definition of the target host: "the population of concern to the observer" in the geographic area under study (table ) . a maintenance host will only be relevant to a target population if it can be in contact with and able to transmit the infection to it. the maintenance function represents the capacity to maintain the pathogen within the ecosystem. a maintenance host is a host population (single population) or community/host complex (several sympatric host populations) "in which the pathogen persists even in the complete absence of transmission from other hosts" [ ] . the maintenance function depends on host density, and on intraand inter-host infectious contacts (i.e., a contact leading to infection amongst other intra-host factors; [ ] ). in multihost systems, the notion of a maintenance community in which several populations from different species play a role in the maintenance of the pathogen seems more appropriate than the "reservoir" concept [ , ] for understanding pathogen dynamics. the reservoir concept is still being used in contradictory ways, as discussed by several authors [ ] [ ] [ ] . haydon et al. [ ] extended the definition of reservoir by adding "source populations" that may not be involved in the maintenance of the pathogen but rather in the transmission of the pathogen to the target population. ashford [ ] defined a "liaison host" as linking the reservoir to another host population, with no explicit reference to target populations. we agree with ashford [ ] that source population should not be included in the definition of the reservoir, as this term is strongly linked to the concept of maintenance and because control of infection in the reservoir would be different if targeted at the maintenance or source populations. for example, aiming at controlling the infection in a maintenance vs. a source population might have different outcomes, since the maintenance host could still re-infect the source population in the latter case. to add to the confusion, suzán et al. [ ] presented a new framework to understand patterns in space and time of meta-communities of hosts and parasites. in their first figure they display in red "reservoir species" and in orange "alternative hosts", together "maintaining higher infection of prevalence". clearly, their concept of "reservoir" differs from that of haydon et al. [ ] , who argued that any host involved in the maintenance of the pathogen should be part of the reservoir. the difference in definitions is identical with plowright et al. [ ] : they present domestic horses as potential source populations (defined in the article as "recipient" and "intermediate hosts") of hendra viruses for human populations without considering them as part of the reservoir (presented as the bat community). the extensive use of the "reservoir" concept under multiple definitions and the lack of consensus around the liaison host and source population concepts (revealed by the scarcity of use of these two last terms in the literature) requires a refined conceptual framework and definitions. agreeing with others [ , ] , we thus prefer to use only maintenance host or community, a term that refers better to the dynamic aspect of the functional role than the static notion of a reservoir [ , ] . although the maintenance-target host relationship and its link with the maintenance function have been properly defined, the function of pathogen transmission to the target host needs a clearer definition. interspecific pathogen transmission is of crucial importance for infectious disease management. disease control can target the maintenance host to stop pathogen maintenance and circulation in the ecosystem (i.e. targeting the maintenance function); however, as this option is often unfeasible (for practical or ethical reasons, notably concerning wildlife populations), one could also try to break the transmission pathway that brings the pathogen to the target host. we therefore define the transmission function as the capacity to transmit the pathogen to the target host. this function must be separated from the maintenance function, as the maintenance host does not always have infectious contact with the target host. when it has direct contact with the target host, then the maintenance host is implicated in the maintenance and transmission functions. when it does not, a bridge host (table ) can connect (i.e., have infectious contact with) both maintenance and target hosts, "bridging" the gap between them. using this functional definition, the concept of the reservoir as revisited by haydon et al. [ ] and more recently by viana et al. [ ] , does not refer clearly to a single epidemiological function, because it includes maintenance host(s) involved in the maintenance function and potentially in the transmission function as well as non-maintenance population(s) only involved in the transmission function. allocating hosts belonging to the reservoir to specific functional groups that surveillance and/or control can target is therefore difficult and provides an additional reason to focus solely on the maintenance-target hosts. bridge host is therefore used, since (i) the group is distinct from the source population, as bridge hosts do not belong to the maintenance host/community, and the liaison host as a bridge host is always in reference to a maintenance-target population system; and (ii) the word "bridge" is relevant to the definition proposed (e.g. [ ] ). -hosts in which the pathogen persists even in the complete absence of transmission from other hosts [ ] x (x) -brush-tailed possums for bovine tuberculosis in new zealand [ ] -population larger than the critical community size (i.e. size under which the pathogen cannot be maintained in the community) in which the pathogen persists [ ] -white-footed mouse (peromyscus leucopus) for lyme disease in the united states [ ] maintenance host community/ maintenance host complex -one or more epidemiologically connected populations or environments in which the pathogen can be permanently maintained [ ] x (x) -anatids for avian influenza viruses worldwide [ ] -any host complex in which disease persists indefinitely is a reservoir [ ] -amphibian sp. for the trematode ribeiroia ondatrae [ ] -host for which cross species transmission and inter-species transmission are high [ ] bridge host -non-maintenance host population able to transmit a pathogen from a maintenance host/complex to the target population, otherwise not or loosely connected to the maintenance complex (this manuscript) x previous related definitions: -little studied so far -source population: any population that transmits infection directly to the target population [ ] -red deer and domestic pigs for bovine tuberculosis in new zealand [ ] ? -liaison host: incidental hosts that transmit pathogens from a reservoir to another incidental host [ , ] -peri-domestic birds such as swallow sp., sparrow sp., etc. [ ] -spatial vector: host that transport the pathogen to target populations in new locations [ ] -temporal vector: host that can transmit the pathogen to target species across temporal scale [ ] crosses in brackets indicate that maintenance host can participate in the transmission function although this is not a necessary condition. bridge hosts refer therefore to a group of hosts that perform the same epidemiological function for a pathogen that can be targeted by specific surveillance and control interventions. in suzán et al. [ ] , information about whether alternative hosts function as bridge hosts would add an important layer of information to their framework and contribute to the understanding of the spatial spread of parasites. our bridge host definition is closely related to the "spatial and temporal vector" concepts presented by nugent [ ] but unifies them with previous definitions (see above) and broadens them. a bridge host can be defined at the level of a population or a community. bridge hosts may be frequent in disease ecology, but this term has not been explicitly defined and its usage is not common when referring to the transmission function without any role in maintenance function. for example, it would be incorrect to use the term "bridge species" as the role of a bridge host would refer to a specific host population in interaction with other hosts in a given ecosystem (e.g. contact with maintenance or target populations) and at a specific density [ ] ; the host density and the network of interaction between these hosts in another ecosystem would likely be different and would make it unlikely that a species can play the same epidemiological functional role across its range. a clearer conceptual framework is thus needed to guide the identification of bridge hosts and the characterisation of their roles in disease ecology. this framework must also be operationalised if it is to guide the design of hypotheses that can be tested through field protocols to characterise the role(s) of hosts in disease ecology. using the different target-maintenance systems proposed by haydon et al. [ ] , bridge hosts can be included in target-bridge-maintenance systems in several ways ( figure ). according to our definition, a bridge host is involved in the transmission function while not involved in the maintenance function. two main prerequisites must be fulfilled for a host to qualify as a bridge host. the first prerequisite is that the host must be competent for the pathogen (i.e., must be receptive to infection, permit pathogen replication, and be able to excrete it) without being able to maintain it alone, in which case the host would be considered as a maintenance host; or alternatively, the host should be able to mechanically transport the pathogen [ , ] . its competence will influence the capacity of a bridge host to achieve the transmission function: if the bridge host has a short pathogen excretion period, it will be able to transmit the pathogen to a target population only if the time lag between contact with a maintenance and then a target host is shorter than the excretion period, or if the distance between target and maintenance is shorter than the maximum distance that the bridge host can travel during its excretion phase. similarly, for mechanical transmission, the survival of the pathogen on/in the host body part (e.g. skin, hair, mouth, feathers) exposed to the external environment will determine for how long the host can play the bridge role. the second prerequisite is that infectious contacts must occur along the maintenance-bridge-target transmission chain. these will depend on direct and indirect (e.g. environmental transmission) contacts, the mode of transmission of the pathogen, and the site of infection. the basic reproductive number r for the bridge host (not considering here mechanical transmission) should be < as it cannot maintain the infection but its force of infection, dependent on the number and extent of infectious contacts with the target host, can be high. a bridge host that compensates for a lack of infectious contacts between maintenance and target hosts can operate across different dimensions: spatial, temporal, and behavioural. the spatial dimension arises when the bridge host creates a spatial link between the separate areas in which the maintenance and the target host populations occur. this dimension typically refers to the situations developed below for wild birds and avian influenza. it has been defined as a "spatial vector" by nugent [ ] when considering the role of feral pigs (sus scrofa) in the epidemiology of bovine tuberculosis (btb) in new zealand. the temporal dimension arises when the pathogen can persist (but not be maintained indefinitely) in the bridge host for a period of time longer than in the maintenance host or during a distinct season; this has been well described by nugent [ ] as a "temporal vector", for example when red deer (cervus elaphus) transmit mycobacterium bovis to possum populations that are controlled to levels that are well under the critical community size for btb maintenance. the behavioural dimension exists when the absence of contact between sympatric maintenance and target hosts is compensated for by another host that has infectious contacts with both. situations may occur in which the microhabitat preferences and behaviours of maintenance and target hosts mean that they do not come into direct contact despite using the same locations on a daily basis. bats, for example, are believed to be the maintenance host for ebola, and can be sympatric with people; but ebola transmission from bats to humans is enhanced by the great apes (whose susceptibility to ebola seems to indicate that they are not maintenance hosts) which feed with bats and are fed upon by humans [ ] . it is interesting to note that in all cases, even a r close to zero (approximating a dead-end host) could still be important for the transmission function: the capacity to excrete the pathogen for a few hours, associated with some form of dispersal, may be sufficient for a bridge host to come into contact with the target host and infect it. for pathogens like ebola, the range of hosts that is classically considered to be important in disease ecology may have to be broadened by including hosts that are able to transmit the pathogen over short time-and space-scales. these hosts are commonly considered as playing no role in pathogen ecology and are called dead-end hosts (e.g., most wild avian hosts for avian influenza virus -aiv -apart from anseriformes and charadriiformes). amongst the multitude of those dead-end hosts, the bridge host perspective can identify some that do play a role in disease ecology. with this framework in place, we next turn to the question of how bridge hosts can be identified in the multihost context of aiv epidemiology and suggest an operational framework (partially implemented in [ ] ) that can figure definition of different target-bridge-maintenance systems (adapted from haydon et al. [ ] ). a represents the simplest maintenance-bridge-target system. in a', the maintenance and target populations are less connected (frequency/intensity of infectious contacts) than between the maintenance-bridge-target populations. in b, mitigation strategies aimed at one bridge host cannot fully control pathogen transmission to the target host because of the alternative bridge host's pathway. if both maintenance populations were in contact with both bridge hosts (i.e. if dashed arrows exist), controlling contacts between the target population and bridge hosts should be simpler than other control options. in b', according to our definition, z is not considered as a bridge population as it belongs to the maintenance community. in c, stopping contacts between the maintenance population and the target population by acting on one of the two bridge hosts would not be enough to stop transmission, which can still occur through the second bridge host. d is a special case of b, understanding the complexity of the maintenance community is not necessary to control the pathogen transmission risk to the target population, which can be achieved through the control of arrows connecting the bridge host. in e, none of the host populations can sustain the infection by itself and according to our definition, u is not considered as a bridge population as it belongs to the maintenance community. in f, the bridge host connects the target population with another maintenance host creating a system with a maintenance meta-population, which could change the epidemiological dynamics of the system and the probability of success of intervention strategies (e.g. vaccination coverage to achieve control of the infection in the target population). g is a special case where two bridge hosts are necessary to achieve the transmission function. good knowledge of the ecological interactions in the ecosystem will be necessary to identify such complex interactions between bridge hosts. enhance disease ecology as well as pathogen surveillance and control. waterfowl (defined here as ducks, geese, waders, gulls, and terns) constitute the maintenance hosts for low pathogenic avian influenza viruses (lpaiv) [ ] . aiv represent major threats to poultry production when strains originating from wild birds evolve from low to high pathogenicity in the poultry (target) populations [ ] . the transmission of lpaiv between the wild bird maintenance community and domestic populations is therefore crucial to managing the sanitary and economic impacts of the disease. in this section, the risk of lpaiv spillover to poultry populations from the maintenance populations will be used as an example. when poultry are confined in farms or buildings, their direct contacts with the maintenance waterfowl community, which mainly lives in wetlands and on coastal shorelines, are believed to be limited due to spatial segregation between populations. many outbreaks of highly pathogenic aiv outbreaks have nonetheless occurred in domestic poultry production systems. it is therefore suspected that bridge hosts play a role in transmitting waterfowl-derived strains of aiv to poultry populations. the ability of wild birds to travel long distances, and their ubiquity in most habitats, facilitate the potential for wild bird species to act as bridge hosts. several constraints limit a better understanding of aiv ecology in bird communities: ) high host diversity, that can include several hundred species in a given ecosystem; ) the costs of diagnostic techniques that limit the number and type of samples (e.g. cloacal/tracheal swabs, blood) that can be analysed; and ) the impossibility of randomly sampling from bird communities because of bias in capture techniques (e.g. walk-in traps, mist-nets). as a consequence, the information available on most wild bird species is scarce and has been obtained mostly from by-catch (i.e. captured non-targeted species) of studies investigating aiv in maintenance waterfowl, resulting in small sample sizes that are inadequate to provide epidemiological understanding of the host roles in aiv ecology in africa [ ] . the following framework used in a recent study [ ] and here developed in detail, aims at first gathering/collecting available ecological and epidemiological information; second, at synthesizing this information to provide a priority list of species that act as potential bridge hosts; and finally, at undertaking targeted sampling that can determine the competence of the high priority species and revisit the framed hypotheses. the range of methods available to characterize host competence for aiv and contact patterns between maintenance, potential bridge and target host populations is drawn from the fields of epidemiology and avian ecology ( table ) . none of these methods alone is sufficient to identify a bridge host in a given ecosystem [ ] . molecular epidemiology (e.g. gene sequencing after virus isolation) could in principle be used to identify bridge species but it is very unlikely that related strains from three different host populations (i.e., maintenance, bridge and target hosts) are concurrently isolated except perhaps during a localised aiv outbreak. virological surveillance (e.g. polymerase chain reaction -pcr techniques) can provide information about host contacts between potential bridge and maintenance hosts if data are collected close to wetlands where waterfowl communities are known to occur. serological investigation (e.g. elisa tests) can be cheaper than virological testing but provide less information on the timing of the infection [ , ] . however, a combination of epidemiological and ecological methods could provide the necessary information to infer the bridge role of a given host population. taking into account these constraints, the proposed framework aims, first, to narrow the large number of species by ranking the most probable potential bridge hosts based on proxies of host competence and/or contacts between maintenance, target and potential bridge hosts. this step can be achieved using (or combining) available published field (e.g. [ , [ ] [ ] [ ] ) and experimental epidemiological studies (e.g. [ , ] ). however, most aiv experimental studies have concentrated so far on a very limited set of species (e.g. for lpai [ , ] and for hpai [ , ] ). reviewing available pcr viral data within a given area or region can provide information on the range of host species with a competence for aiv. for example, in sub-saharan africa, the available databases are poor representations of existing avian diversity (only . % of all african species have been sampled, additional files and , and only a few species were tested with a sample size that would be sufficient to detect % aiv prevalence). this exercise can help with ranking the species or groups of species based on the rate of infection, which provides an initial prioritization list for future investigation (additional file ). however, one shortcoming of pcr data is to link detection of genetic material and state of infectiousness of the sampled individual [ ] , an issue that is often overlooked but particularly important for the identification of bridge hosts. the first step of the proposed framework must also incorporate ecological data that provide information about the presence/abundance of potential bridge hosts in the ecosystem and their potential contacts with maintenance and target hosts. however, it is a challenge to provide evidence that contacts ( ) occur; and ( ) result in successful virus transmission. different types of data can be used or collected, each with its own strengths and weaknesses: life history traits (e.g., abundance, gregarism, foraging and migratory behaviour) obtained from the literature can be used as risk factors for contacts between wild and domestic birds or exposure to infection [ , ] ; contacts between wild and domestic birds can be estimated using satellite telemetry [ ] ; capture-recapture techniques indicate population size (e.g. using colour rings at a local scale) [ ] ; and observations at focal points that are at wild/ domestic bird interfaces (e.g. around poultry production building) can be used to quantify interactions [ ] . the second step is to synthesize the ecological and/or epidemiological data to rank bird species according to the likelihood that they play a bridge role in the ecosystem under study. risk analysis can provide such a tool [ , [ ] [ ] [ ] and may be particularly important when no information is available for an ecosystem, or prior to a field survey, by highlighting the populations that could be targeted preferentially. once the bridging potential of different species has been evaluated, the third step of the framework consists in testing the host competence of the most likely bridge hosts in the ecosystem through targeted sampling. for example, caron et al. [ ] applied this framework in a southern african ecosystem and identified bridge hosts by combining bird counts with selected sampling and pcr testing. targeted sampling facilitates the concentration of resources to obtain adequate sample sizes and relevant epidemiological information and comes in place of the practice of blind sampling from wild bird communities, which is usually biased by capture techniques. hypotheses can be revisited iteratively as more is learned about the potential of highly ranked species to act as bridge hosts. this approach can also lead to the detection of inconsistencies in the initial model (e.g., the definition of the maintenance community) and the necessity to revisit it [ ] . avian influenza provides a good example of a case in which paying conceptual and practical attention to bridge hosts can enhance our understanding of pathogen dynamics in multi-host systems. although the use of the bridge host concept may not be relevant for all multi-host systems, it has the potential to contribute to structuring investigations on the ecology of emerging pathogens shared at wildlife/livestock interfaces. to illustrate this point we present two additional examples of multi-host systems. in the first, ebola in west africa, understanding could be improved by the use of the conceptual framework developed here. in the second and better-known system, bovine tuberculosis in new zealand, bridge hosts have been identified and are an important component of the problem. ebola virus spilled over in early in west africa from an unknown animal to the human index case. knowledge of ebola ecology is still limited, despite the first outbreak having being reported in . current understanding points at bats (mammalia: chiroptera) as potential maintenance hosts, and contact between humans and some bat species occurs through the bushmeat industry [ ] as well as via bat droppings and occasional cases of sick bats that are handled by humans [ , ] . however, embracing the functional approach presented here makes sense to look for potential bridge hosts that could link maintenance bats and humans. a priori, scavenging pigs, dogs, other non-maintenance bat species and wild antelope can have direct or indirect (e.g. consumption/hunting) contact with humans [ ] . targeted surveillance of such species will provide information on their competence for the virus; and host interaction protocols that identify contact networks with maintenance and target populations can provide information on the potential for viral spread (e.g. [ ] ). once the multi-host system is better understood (case b, c or d in figure ), it may be simpler to try to block transmission pathways from bridge hosts to human populations (e.g. through changes in behavior related to bridge host consumption by people) than to control the pathogen in the maintenance hosts. [ ] [ ] [ ] [ ] risk analysis x x x [ ] [ ] [ ] serological investigation x x x xx [ , , ] virological investigation xx xx xx xx xx [ , , , , , , ] telemetry study xxx xxx xxx [ ] bird ringing and monitoring xx x x [ ] bird counts xx xx x [ , , , ] molecular epidemiology xx xx xx xx xx xxx [ , ] as the number of crosses increases in the first columns the methods provide better ecological or epidemiological information; in the last columns, cost increases as the number of crosses increases. a similar yet less complex example was recently developed [ ] , indicating that domestic horses could be "bridge hosts" for hendra viruses between bats (maintenance host) and humans (target host) even if it is not yet known if horses could maintain the virus or just act as a bridge between bats and humans [ ] . as a second example of the utility of the bridge host framework, nugent [ ] offers a comprehensive description of the btb multi-host system in new zealand. the cattle industry in new zealand suffers from continuous spillover of the btb mycobacterium from the maintenance host, the brush-tailed possum (trichosurus vulpecula). the control of possum populations by depopulation is mainly implemented in areas around farms that are at high-risk of transmission to cattle, leaving high densities of possums in more distant forest and providing a gradient of btb prevalence. this apparently efficient strategy is, however, thwarted by three potential bridge hosts (feral pigs sus scrofa, red deer cervus elaphus, and feral ferrets mustela furo) that are involved in transmission (case g in figure , called "link-host" in the article but lacking a more conceptual definition). infected pigs and deer with large home ranges may leave the forest to die (or be hunted) around farms, providing an opportunity for ferrets to become infected when feeding on carcasses and subsequently infecting cattle or possums. this study is particularly interesting for reasons: ( ) the complexity and low probability of the chain of events leading to infection of the target population do not prevent btb occurrence and the failure of disease control; ( ) disease control targeted at the maintenance population prevents the transmission link between the maintenance and target hosts but the transmission pathways built by bridge hosts (case a' in figure ) reduce the effectiveness of control, proving the importance of considering this epidemiological function and host role; and ( ) the plasticity of the roles of host populations in disease epidemiology, which is heavily influenced by the environmental, ecological and anthropological context. the concepts of transmission function and bridge host contribute to a better understanding of disease ecology in multi-host systems by clarifying the epidemiological processes that are relevant for disease transmission and maintenance. this perspective fits better with the way that people operationalize the complexity theory and makes it easier to develop models of these systems. when maintenance and target hosts are not in direct contact, pathogen transmission relies on successive infectious contacts along the chain of maintenance, bridge and target hosts. bridge hosts can play a pertinent and legitimate role in disease ecology and could become the targets for surveillance and control for some multi-host systems. for example, in some ecosystems, domestic bird populations are rarely in direct contact with wild waterfowl populations but phylogenetic analyses have indicated that most precursors of hpaiv in gallinaceous poultry have originated from wild waterfowl [ ] , suggesting that bridge hosts play a role in aiv transmission at the wild/domestic bird interface. more recently, evidence supporting a role for some passerines (finches, sparrows) in the transmission of the avian-origin human influenza a (h n ) to human and poultry in china [ ] suggests a potential role for passerines as bridge hosts between poultry and humans. the functional approach emphasizes the need to focus on transmission pathways between hosts (and their directionality) instead of relying solely on intrinsic host properties (e.g. density, shedding capacity) [ , ] . the presence of a target host defines directionality in the transmission processes and implies a network of interconnected hosts with different epidemiological roles. our framework thus provides a better empirical approach to some kinds of epidemiological problems, such as the risk of spread of a specific pathogen towards a target population or the potential for disease emergence in emerging disease hotspots. the maintenance and transmission function concepts can be related to the roles of vectors in vector-borne disease ecology. blood-feeding arthropod vectors that transmit a pathogen between hosts [ ] may be involved in distinct epidemiological functions, including the transmission function. the term "bridge vector" has already been used (e.g. [ , ] ) to group mosquitoes that transmit west nile virus to humans (here the target population). however, so far, the distinction between the maintenance and transmission function has not been properly defined. this distinction could be important if maintenance and bridge vectors are different species, opening different control strategy options (i.e. on the maintenance or on the bridge hosts). the identification of bridge hosts for a given pathogen in a given ecosystem has consequences for disease management, surveillance and control. once bridge hosts are known, managers can adopt mitigation strategies specifically aimed at reducing contact between the target and the bridge populations. in the case of aiv, this mitigation can be achieved through strengthening biosecurity measures or decreasing the quantity of attractors on the farm (e.g. water sources or open feedlots) [ ] . the adoption of adequate management measures targeting contacts between maintenance, bridge and target hosts is also more environmentally acceptable than controlling (wild) host populations. the distinction between maintenance and bridge hosts may under some circumstances be difficult. in the case of aiv, for example, our current level of knowledge about the maintenance hosts and the apparent lack of contact in some ecosystems between the maintenance community and the target populations suggest a role for bridge hosts. the identification of hosts that do not fit into either maintenance or target host groups, as in [ ] , raises two possibilities: either these susceptible hosts act as bridge hosts, or they may act as previously unknown maintenance hosts for aiv epidemiology. to differentiate between these two hypotheses may require focused experimental research, for example by using infection of captive animals to determine their capacity to maintain the virus. other approaches using meta-analysis of existing data sets have also been proposed [ ] . in both cases, our conceptual framework helps with framing hypotheses based on current knowledge and using empirical tests to either confirm these hypotheses or call for a revision of our understanding of the epidemiological system (e.g. this host is not a bridge host and therefore has no (or another) role in the local context). our framework does have some weaknesses. in particular, proving that a bridge host in a complex multi-host system where maintenance communities are composed of numerous interacting populations does not take part in the maintenance function (i.e. that removing the bridge host will not drive the pathogen to extinction, according to haydon et al. [ ] ) may necessitate an experimental design that would be difficult to achieve in practice [ ] . in addition, only cases in which maintenance and target populations are not in contact have been considered so far. if they are loosely in contact (case a' in figure ), the frequency and efficacy of contacts between different pairs (maintenance-target, maintenance-bridge and bridgetarget) would need to be weighted against each other. decreasing the maintenance-target contacts through management will reveal the relative importance of bridge-target contacts and could require interventions in order to efficiently stop pathogen transmission (as in the case of control of possums for btb in new zealand mentioned earlier). finally, we have assumed that a bridge host must be competent for the pathogen but in some cases simple mechanical transmission (e.g., a bird carrying the virus on its feathers [ ] ) may be possible, relaxing the prerequisite on host competence for the bridge host. the development of complex human/livestock/wildlife interfaces, due to the encroachment of human activities within natural ecosystems, triggers new epidemiological dynamics that may permit a range of wild or domestic bridge hosts to link maintenance communities with new target hosts [ ] . we would expect that domestic species and newly farmed or traded wildlife species will increasingly play bridge host roles in the emergence of new zoonoses. the epidemiology of ebola, sars, lyme disease, and h n aiv, for example, are not yet fully understood but are known to involve multiple hosts. we believe that introducing our definitions and operational framework into research and surveillance could contribute to more efficient use of resources to fill some knowledge gaps. our approach builds on that of haydon et al. [ ] and refines it to take into account potential circumstances under which an extra conceptual development is necessary. whether this extra development will be necessary in many multi-host systems or will be used only under exceptional circumstances will be answered by studies to come. the examples given here indicate that they could be used for at least a few important diseases. the recent appearance in the epidemiological literature of similar concepts [ , , ] that are not always placed soundly within a conceptual framework and/or ignore previous definitions suggests also the need for a consolidated review and refinement of these concepts and definitions. while no individual element of our proposed framework is new, it is clear from our discussion above that approaching the problem of understanding multi-host disease systems from a more integrated, functional perspective has the potential to offer a wide range of valuable insights into both epidemiology and its applications to pathogen control. our approach, which requires both epidemiological and ecological approaches (and also social science approaches when the human host is considered) fits well within current initiatives that call for more transdisciplinary integration between the health sciences and other fields of research. finally, the global fight against emerging infectious diseases is increasingly focused on identifying potential emerging pathogens from high-risk maintenance hosts (e.g., bats and rodents, [ , ] ). recent advances in genetics and genomics have increased drastically the pace at which new micro-organisms are discovered and identified [ ] . but adding new names to the list of parasites and pathogens does not provide information on which of these microorganisms might present a significant threat to animal or human health. a maintenance population hosting a large range of potentially new emerging pathogens does not constitute a threat for target populations if no transmission route exists between the maintenance and target populations. focusing on pathogen transmission pathways, including potential hosts bridging the gap between maintenance and target populations, will help to guide "pathogen hunting" approaches as functional ecology complements taxonomy. such an approach will help to guide high-throughput sequencing tools towards key hosts within a given epidemiological context, increasing the efficiency of surveillance and control efforts. epidemiology and public health unit contrasting spatial patterns of taxonomic and functional richness offer insights into potential loss of ecosystem services infectious diseases of humans: dynamics and control causal inference in disease ecology: investigating ecological drivers of disease emergence experimental infection of north american birds with the new york strain of west nile virus the ecology of infectious disease: effects of host diversity and community composition on lyme disease risk epidemiological interaction at the wildlife/livestock/human interface: can we anticipate emerging infectious diseases in their hotspots? a framework for understanding emerging diseases processes in their hot spots linking avian communities and avian influenza ecology in southern africa using epidemiological functional groups assembling evidence for identifying reservoirs of infection identifying reservoirs of infection: a conceptual and practical challenge when is a reservoir not a reservoir? maintenance, spillover and spillback transmission of bovine tuberculosis in multi-host wildlife complexes: a new zealand case study from superspreaders to disease hotspots: linking transmission across hosts and space community epidemiology framework for classifying disease threats what it takes to be a reservoir host metacommunity and phylogenetic structure determine wildlife and zoonotic infectious disease patterns in time and space ecological dynamics of emerging bat virus spillover biodiversity decreases disease through predictable changes in host community competence situation-based survey of avian influenza viruses in possible "bridge" species of wild and domestic birds in nigeria the housefly, musca domestica, as a possible mechanical vector of newcastle disease virus in the laboratory and field the digestive tract of the whiteback griffon vulture and its role in disease transmission among wild ungulates wildlife and emerging zoonotic diseases: the biology, circumstances and consequences of cross-species transmission bridge hosts for avian influenza viruses at the wildlife/domestic interface: an eco-epidemiological framework implemented in southern africa global patterns of influenza a virus in wild birds evolutionary biology, community ecology and avian influenza research the ecology of influenza a viruses in wild birds in southern prevalence of antibodies to type a influenza virus in wild avian species using two serologic assays evaluation of a commercial blocking enzyme-linked immunosorbent assay to detect avian influenza virus antibodies in multiple experimentally infected avian species influenza a viruses of migrating wild aquatic birds in north america serological evidences of influenza a virus infection in antarctica migratory birds spatial, temporal, and species variation in prevalence of influenza a viruses in wild migratory birds influence of body condition on influenza a virus infection in mallard ducks: experimental infection data avian influenza in shorebirds: experimental infection of ruddy turnstones (arenaria interpres) with avian influenza virus experimental infection of swans and geese with highly pathogenic avian influenza virus (h n ) of asian lineage experimental assessment of the pathogenicity of eight avian influenza a viruses of h subtype for chickens, turkeys, ducks and quail infectivity of avian influenza virus-positive field samples for mallards: what do our diagnostic results mean? understanding the ecological drivers of avian influenza virus infection in wildfowl: a continental scale study across africa use of observed wild bird activity on poultry farms and a literature review to target species as high priority for avian influenza testing in regions of canada characterizing the interface between wild ducks and poultry to evaluate the potential of transmission of avian pathogens a comparative analysis of movements of southern african waterfowl (anatidae), based on ringing recoveries estimating dynamic risk factors for pathogen transmission using community-level bird census data at the wildlife/domestic interface wild bird movements and avian influenza risk mapping in southern africa ornithological data relevant to the spread of avian influenza in europe (phase ): further identification and first field assessment of higher risk species fruit bats as reservoirs of ebola virus bats: important reservoir hosts of emerging viruses transmission of ebola virus from pigs to non-human primates understanding pathogen transmission dynamics in waterbird communities: at what scale should interactions be studied? molecular analysis of avian h influenza viruses circulating in eurasia in - : detection of multiple reassortant virus genotypes possible role of songbirds and parakeets in transmission of influenza a(h n ) virus to humans differential sources of host species heterogeneity influence the transmission and control of multihost parasites relationship between pace of life and immune responses in wild rodents ecology: from individuals to ecosystems -, th edn west nile virus risk assessment and the bridge vector paradigm culex pipiens (diptera: culicidae): a bridge vector of west nile virus to humans sampling strategies and biodiversity of influenza a subtypes in wild birds isolation of influenza a viruses from wild ducks and feathers in minnesota conservation and development interventions at the wildlife/livestock interface: implications for wildlife, livestock and human health emerging infectious diseases: threats to human health and global stability host range and emerging and reemerging pathogens discovering the phylodynamics of rna viruses persistence of low pathogenic avian influenza virus in waterfowl in a southern african ecosystem influenza a viruses in waterbirds in africa investigating avian influenza infection hotspots in old-world shorebirds isolation of a low pathogenic avian influenza virus (h n ) from a black kite (milvus migrans) in egypt in circulation of avian influenza viruses in wild birds in inner niger delta characterization of h n avian influenza virus isolated from a wild white pelican in zambia reassortant low-pathogenic avian influenza h n viruses in african wild birds additional file : virus detection in african non-maintenance wild bird populations (order and family level). this file describes the methodology that was used to gather all the relevant information on rt-pcr aiv results of non-anseriformes and non-charadriiformes species in africa and provides the summary of findings at the bird order and family level. [ , , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] .additional file : aiv rt-pcr results for wild birds sampled in africa until . this table displays detailed results of wild bird species and families sampled for aiv (rt-pcr) in africa until following the gathering of data as described in additional file . the authors declare that they have no competing interests. ac drafted the first version of the manuscript after in-depth discussions with the various authors about the concept and framework developed in this manuscript. jc, gsc, mdgw and ng commented on various versions of the manuscript. all authors read and approved the final manuscript. this article was made possible by the involvment of authors in three projects: the gripavi project sponsored by grants from the french ministry of foreign affairs, the tcp of fao through additional grants from the government of france, and the usaid-sponsored (through the wildlife conservation society) gains project. we are grateful to the numerous epidemiologists, veterinarians and field assistants who participated in field operations. this work was conducted within the framework of the research platform "production and conservation in partnership", rp-pcp and the ahead initiative.author details key: cord- -z vwovw authors: saier, milton h. title: are megacities sustainable? date: - - journal: water air soil pollut doi: . /s - - - sha: doc_id: cord_uid: z vwovw nan increasing numbers of people are moving to cities, causing urban populations to expand. in , only % of the world_s people lived in cities, but by , the percentage had increased to %. soon, over % of the world_s people will live in cities. several questions arise related to this movement: ( ) how rapidly are people moving to cities? ( ) what are the benefits to having a larger urban population? ( ) what are the detriments of such a move? ( ) are city folks taking major risks compared with people living in rural areas? ( ) if so, what are these risks, and how can they be avoided? recently, b.r. gurjar published an article entitled "mega cities: city-states of the future (gurjar, ) ." in this article, he points out that cities contribute enormously to a nation's economy provided that they can manufacture or otherwise generate products that are of global value. in fact, some cities specialize in just one or a few commercial products, say, automobiles, computers, or drugs, so that the people of that city depend on a relatively small number of industrial enterprises for jobs. moreover, the primary product produced by a particular urban population may result from the presence of a single company, and its presence in that city reflects the decisions of just a few executives. decisions to hire, fire, maintain or close a facility can therefore be made on short notice even though they affect the lives of thousands. gurjar defines a megacity as one that has a population of over , , . while there were only two megacities in , new york and tokyo, with populations of . and . million, respectively, we now have such urban centers worldwide with populations sometimes exceeding , , . this tremendous rise results both from astronomical global birth over death rates and from the migration of rural populations to the cities. let_s examine these two primary causes in more detail. every day, there are over , more people on earth than the day before; , is the minimal number of births over deaths worldwide in a single day! moreover, about % of the world_s rural population moves from the country to the cities every two years. this amounts to an average increase in the urban population of roughly million people per year, due solely to migration. urban fertility rates, generally lower than rural fertility rates, but nevertheless appreciable, particularly in third world countries, plus the tremendous influx of people from the country, accounts for the rise in the urban population. in contrast to country life, cities depend on extensive infrastructural support systems. these pro-vide food, water, energy, transportation, lodging, information transfer, recreation and other necessities. the sudden loss of a city_s infrastructure due to a natural or man-created disaster would be expected to promote human suffering of a magnitude that far surpasses anything that could have occurred in the past with a less centralized population living in a rural setting. this fact emphasizes one of the primary risk factors associated with urban life. past examples of urban disasters abound: the great san francisco earthquake and fire of caused thousands of deaths and tremendous loss of property. in fact, most of the city was destroyed, and two-thirds of the population, some , people, suddenly found themselves homeless. the same disaster today, occurring in any one of our megacities, could cause -to -fold more damage, homelessness and loss of life. in this regard, it is important to note that in addition to san francisco, los angeles and delhi, which fall within major quake zones, have made no provision for the millions of people who would lose their homes if such a quake were to occur. the two hurricanes that hit the gulf coast last year devastated new orleans and biloxi, and would have done the same in galveston and houston if the winds hadn_t shifted at the last moment. global warming is believed to have greatly increased the intensity and duration of these hurricanes. such storms are likely to become increasingly destructive with time. the devastation observed for new orleans will become a recurrent theme as the oceans increase in temperature and sea levels rise. all coastal megacities are potential targets, and most megacities are coastal. extremes of weather conditions can bring sudden, unexpectedly heavy precipitation. heavy rainfall and consequent mudslides and wall collapse in mumbai, india brought the city to a virtual standstill in one day, on july , . thirty-seven inches of rain fell on the city within a -h period, more than had ever been observed for an indian city in all of recorded time. thousands were killed. was this another consequence of global warming, or was it merely a chance event? if the former, then such extreme occurrences can be anticipated to be more frequent in the future. in fact, this is exactly what the experts on climate change have been predicting. the heat wave in europe led to tens of thousands of human deaths as well as extensive wild fires, particularly in spain and portugal. the in-creased incidences of forest fires in the western united states over the past few years, especially during the heat wave of , resulted in loss of natural resources as never observed previously in recorded history. global warming again played a major role. with a global economy, such events almost anywhere in the world can have adverse effects on the security of urban life. consequences of war are often devastating. one atomic bomb can ruin the whole day for millions of people living in close proximity in a megacity. the same bomb dropped in the country would have longterm environmental consequences, but would not cause comparable loss of human life and property. moreover, militant countries usually target cities, rarely the country. war is just one of many potential man-promoted forms of devastation that affect urban populations far more than rural populations. with the growth of urban populations, dependencies on modern technologies increase. estimates indicate that for the urban u.s. population, a majority of food products travel over a thousand miles before reaching the consumer. we depend on a truly global economy where coffee comes from south america, pineapples are from hawaii, apples are from the state of washington, and citrus comes from california or florida. interference with crop production, transportation or storage can cause major hardships to urban populations. such hardships are not felt by rural populations that produce their own food locally. moreover, using our current means of transportation, the further a product is transported, the more fossil fuels must be burned, contributing to global warming. a global economy means sensitivity to natural and man-promoted disasters. regardless of whether a war, a hurricane or economic manipulation is responsible, millions of people can lose their sense of security and their lives. disasters of this magnitude were unheard of in the past. food and water availability are interlinked. affluent populations tend to eat more meat, much to the detriment of their own health and the environment. raising meat in the u.s. is responsible for one-quarter of the land use and nearly one-half of the water consumption. the statistics are similar in many other countries. the harmful impact on the environment of eating meat is estimated to be times that of eating plant products. while some have claimed that urbanization should allow for reforestation and restoration of natural habitats, the sobering facts suggest that positive effects will be minimal compared to the negative ones. it is well established that disease transmission is greatly enhanced when the population density increases, particularly when and where squalid conditions exist. in many megacities worldwide, the unavailability of sterile water and/or adequate sewer systems promotes the likelihood of epidemics. this probability is enhanced by the continual appearance of new human diseases such as aids, sars, and avian flu as well as by the reoccurrence of old diseases such as tuberculosis, cholera and plague, due to the evolution of drug resistant fungi, protozoans, bacteria and viruses. moreover, global warming, with ambient temperatures approaching body temperatures, will facilitate disease transmission, particularly those mediated by insects and microbes. combine these problematic situations with unanticipated natural or man-made disasters that can compromise infrastructural stability, and the consequences to an urban population can be devastating. increased local pollution is still another consequence of urbanization. today, children raised in los angeles have % less lung capacity than kids raised in a rural environment. local air pollution is the cause. statistical analyses have also shown that urban populations suffer from substantially higher cancer and disease frequencies than rural populations. although causal relationships have been less easy to establish, all racial types suffer from increased rates of these diseases when living in cities. the causes are not difficult to imagine. as the numbers of megacities in the world increase, environmental and health risks increase proportionally causing a rise in mortality rates. only a single humane solution is likely to provide longterm relief from this precarious situation: reduction in the human population. while conversion to more sustainable lifestyles and minimizing pollution will help, these advances can only be considered to be short-term solutions. as long as human populations continue to increase and become concentrated in urban centers, both immediate health problems and long-term environmental consequences will persist. moreover, the unfortunate consequences of unexpected but increasingly probable disasters can be expected to be proportional to population size. for achievement of human health, safety and a sustainable metropolis, the solution requires diminution of the human global population. numerous studies conducted worldwide have shown that this goal is attainable through the free provision of birth control and abortion services worldwide. such a prospect is eminently achievable in today_s societies, provided that wealthy countries are willing to make the financial means available to third world countries. this is estimated to cost a mere $ billion per year, a small fraction of what the u.s. now spends for war and destruction in iraq with no benefit to anyone. when birth control and abortion are provided, and women make the decisions, fewer babies are born, regardless of the social, economic and educational levels of the women involved. although the need to promote this all-important goal is now recognized by all of the experts, implementation of such a program has, in the past, been thwarted by irrational thought. educated citizens of all developed countries have the responsibility to come out of the closet, become vocal, and confront the mighty irrational elements of society. only socially responsible politicians can be tolerated. a major effort must therefore aim to overcome irrationality through logic, deductive reasoning and education so as to promote the best possible course of action. selfish, short-term interests must be recognized for what they are. maximal benefit for all world citizens must be sought. mega cities: city-states of the future. the financial express key: cord- -tpqsjjet authors: nan title: section ii: poster sessions date: - - journal: j urban health doi: . /jurban/jti sha: doc_id: cord_uid: tpqsjjet nan food and nutrition programs in large urban areas have not traditionally followed a systems approach towards mitigating food related health issues, and instead have relied upon specific issue interventions char deal with downstream indicators of illness and disease. in june of , the san francisco food alliance, a group of city agencies, community based organizations and residents, initiated a collahorarive indicator project called rhe san francisco food and agriculture assessment. in order to attend to root causes of food related illnesses and diseases, the purpose of the assessment is to provide a holistic, systemic view of san francisco\'s food system with a focus on three main areas that have a profound affect on urban public health: food assistance, urban agriculture, and food retailing. using participatory, consensus methods, the san francisco food alliance jointly developed a sec of indicators to assess the state of the local food system and co set benchmarks for future analysis. members collected data from various city and stare departments as well as community based organizations. through the use of geographic information systems software, a series of maps were created to illustrate the assets and limitations within the food system in different neighborhoods and throughout the city as a whole. this participatory assessment process illustrates how to more effectively attend to structural food systems issues in large urban areas by ( t) focusing on prevention rather than crisis management, ( ) emphasizing collaboration to ensure institutional and structural changes, and ( ) aptly translating data into meaningful community driven prevention activities. to ~xplore the strategies to overcome barriers to population sample, we examined the data from three rapid surveys conducted at los angeles county (lac). the surveys were community-based partic· patory surveys utilizing a modified two-stage cluster survey method. the field modifications of the method resulted in better design effect than conventional cluster sample survey (design effect dose to that if the survey was done as simple random sample survey of the same size). the surveys were con· ducte~ among parents of hispanic and african american children in lac. geographic area was selected and d .v ded int.o small c~usters. in the first stage, clusters were selected with probability proportionate to estimated size of children from the census data. these clusters were enumerated to identify and develop a list of households with eligible children from where a random sample was withdrawn. data collectmn for consented respondents involved - minutes in-home interview and abstraction of infor· ma~ion from vaccine record card. the survey staff had implemented community outreach activities designed to fost~r an~ maintain community trust and cooperation. the successful strategies included: developing re.lat on .w. th local community organizations; recruitment of community personnel and pro· vide them with training to conduct the enumeration and interview; teaming the trained community introduction: though much research has been done on the health and social benefits of pet ownership for many groups, there have been no explorations of what pet ownership can mean to adults who are marginalized, living on fixed incomes or on the street in canada. we are a community group of researchers from downtown toronto. made up of front line staff and community members, we believe that community research is important so that our concerns, visions, views and values are presented by us. we also believe that research can and should lead to social change. method: using qualitative and exploratory methods, we have investigated how pet ownership enriched and challenged the lives of homeless and transitionally housed people. our research team photographed and conducted one-on-one interviews with pet owners who have experienced home· lessncss and live on fixed incomes. we had community participation in the research through a partnership with the fred vicror centre camera club. many of the fred victor centre camera club members have experienced homelessness and being marginalized because of poverty. the members of the dub took the photos and assisted in developing the photos. they also participated in the presenta· tion of our project. results: we found that pet ownership brings important health and social benefits to our partici· pants. in one of the most poignant statements, one participant said that pet ownership " ... stops you from being invisible." another commented that "well, he taught me to slow down, cut down the heavy drugs .. " we also found that pet ownership brings challenges that can at times be difficult when one is liv· ing on a fixed income. we found that the most difficult thing for most of the pet owners was finding affordable vet care for their animals. conclusion: as a group, we decided that research should only be done if we try to make some cha.nges about what we have learned. we continue the project through exploring means of affecting social change--for example, ~eti.tions and informing others about the result of our project. we would like to present our ~mdmgs and experience with community-based participatory action resea.rch m an oral. presentarton at yo~r conference in october. our presentation will include com· mumty representation ~f. both front-hne staff and people with lived experience of marginalization and homdessness. if this is not accepted as an oral presentation, we are willing to present the project m poster format. introduction the concept of a healthy city was adopted by the world health organization some time ago and it includes strong support for local involvement in problem solving and implementation of solutions. while aimed at improving social, economic or environmental conditions in a given community, more significantly the process is considered to be a building block for poliq reform and larger scale 'hange, i.e. "acting locally while thinking globally." neighbourhood planning can he the entry point for citizens to hegin engaging with neighbours on issues of the greater common good. methods: this presentation will outline how two community driven projects have unfolded to address air pollution. the first was an uphill push to create bike lanes where car lanes previously existed and the second is an ongoing, multi-sectoral round table focused on pollution and planning. both dt•monstrate the importance of having support with the process and a health focus. borrowing from traditions of "technical aid"• and community development the health promoter /planner has incorporated a range of "determinants of health" into neighbourhood planning discussions. as in most urban conditions the physical environment is linked to a range of health stressors such as social isolation, crowding, noise, lack of open space /recreation, mobility and safety. however typical planning processes do not hring in a health perspective. health as a focus for neighbourhood planning is a powerful starti_ng point when discussing transportation planning or changing land-uses. by raising awareness on determmants of health, citizens can begin to better understand how to engage in a process and affect change. often local level politics are involved and citizens witness policy change in action. the environmental liaison committee and the dundas east hike lanes project resulted from local level initiatives aimed at finding solutions to air pollution -a priority identified hy the community. srchc supported the process with facilitation and technical aid. _the processs had tangible results that ultimately improve living conditions and health. •tn the united kmgdom plannm in the 's established "technical aid" offices much like our present day legal aid system to provide professional support and advocacy for communities undergoing change. p - (c) integrating community based research: the experience of street health, a community service agency i.aura cowan and jacqueline wood street health began offering services to homeless men and women in east downtown ~oronto in . nursing stations at drop-in centres and shelters were fo~lowed by hiv/aids prevent ~, harm reduction and mental health outreach, hepatitis c support, sleeping bag exchange, and personal tdennfication replacement and storage programs. as street health's progi;ams expanded, so to~ did the agency:s recognition that more nee~ed t~ be done to. address the underl~ing causes of, th~ soct~l and economic exclusion experienced by its clients. knowing t.h~t. a~voca~y ts. helped by . evtd~nce , street he.alt~ embarked on a community-based research (cbr) initiative to dent fy commumty-dnven research priorities within the homeless and underhoused population. methods: five focus groups were conducted with homeless people, asking participants to identify positive and negative forces in their lives, and which topics were important to take action on and learn more about. findings were validated through a validation meeting with participants. results: participants identified several important positive and negative forces in their lives. key positive forces included caring and respectful service delivery, hopefulness and peer networks. key negative forces included lack of access to adequate housing and income security, poor service delivery and negative perceptions of homeless people. five topics for future research emerged from the process, focusing on funding to address homelessness and housing; use of community services for homeless people; the daily survival needs of homeless people and barriers to transitioning out of homelessness; new approaches to service delivery that foster empowerment; and policy makers' understanding of poverty and homelessness. conclusions: although participants expressed numerous issues and provided much valuable insight, definitive research ideas and action areas were not clearly identified by participants. however, engagement in a cbr process led to some important lessons and benefits for street health. we learned that the community involvement of homeless people and front-line staff is critical to ensuring relevance and validity for a research project; that existing strong relationships with community parmers are essential to the successful implementation of a project involving marginalized groups; and that an action approach focusing on positive change can make research relevant to directly affected people and community agency staff. street health benefited from using a cbr approach, as the research process facilitated capacity building among staff and within the organization as a whole. p - (c) a collaborative process to achieve access to primary health care for black women and women of colour: a model of community based participartory research notisha massaquoi, charmaine williams, amoaba gooden, and tulika agerwal in the current healthcare environment, a significant number of black women and women of color face barriers to accessing effective, high quality services. research has identified several issues that contribute to decreased access to primary health care for this population however racism has emerged as an overarching determinant of health and healthcare access. this is further amplified by simultaneous membership in multiple groups that experience discrimination and barriers to healthcare for example those affected by sexism, homelessness, poverty, homophobia and heterosexism, disability and hiv infection. the collaborative process to achieve access to primary health care for black women and women of colour project was developed with the university of toronto faculty of social work and five community partners using a collaborative methodology to address a pressing need within the community ro increase access to primary health care for black women and women of colour. women's health in women's hands community health centre, sistering, parkdale community health centre, rexdale community health centre and planed parenthood of toronto developed this community-based participatory-action research project to collaboratively barriers affecting these women, and to develop a model of care that will increase their access to health services. this framework was developed using a process which ensured that community members from the target population and service providers working in multiculrural clinical settings, were a part of the research process. they were given the opportunity to shape the course of action, from the design of the project to the evaluation and dissemination phase. empowerment is a goal of the participatory action process, therefore, the research process has deliberately prioritized _ro enabling women to increase control over their health and well-being. in this session, the presenters will explore community-based participatory research and how such a model can be useful for understanding and contextualizing the experiences of black women and women of colour. they will address. the development and use of community parmerships, design and implementation of the research prorect, challenges encountered, lessons learnt and action outcomes. they will examine how the results from a collaborative community-based research project can be used as an action strategy to poster sessions v address che social determinants of women health. finally the session will provide tools for service providers and researchers to explore ways to increase partnerships and to integrate strategies to meet the needs of che target population who face multiple barriers to accessing services. lynn scruby and rachel rapaport beck the purpose of this project was ro bring traditionally disenfranchised winnipeg and surrounding area women into decision-making roles. the researchers have built upon the relationships and information gachered from a pilot project and enhanced the role of input from participants on their policy prioriries. the project is guided by an advisory committee consisting of program providers and community representatives, as well as the researchers. participants included program users at four family resource cencres, two in winnipeg and two located rurally, where they participated in focus groups. the participants answered a series of questions relating to their contact with government services and then provided inpuc as to their perceptions for needed changes within government policy. following data analysis, the researchers will return to the four centres to share the information and continue che discussion on methods for advocating for change. recommendations for program planning and policy development and implementation will be discussed and have relevance to all participants in the research program. women's health vera lefranc, louise hara, denise darrell, sonya boyce, and colleen reid women's experiences with paid and unpaid work, and with the formal and informal economies, have shifted over the last years. in british columbia, women's employability is affected by government legislation, federal and provincial policy changes, and local practices. two years ago we formed the coalition ior women's economic advancement to explore ways of dealing with women's worsening economic situations. since the formation of the coalition we have discussed the need for research into women's employabilicy and how women were coping and surviving. we also identified how the need to document the nature of women's employability and reliance on the informal economy bore significanc mechodological and ethical challenges. inherent in our approach is a social model of women's health that recognizes health as containing social, economic, and environmental determinants. we aim to examine the social contexc of women's healch by exploring and legitimizing women's own experiences, challenging medical dominance in understandings of health, and explaining women's health in terms of their subordination and marginalizacion. through using a feminist action research (far) methodology we will explore the relationship between women's employability and health in communities that represent bricish columbia's social, economic, cultural/ethnic, and geographic diversities: skidegate, fort st . .john, lumhy, and surrey. over the course of our year project, in each community we will establish and work with advisory committees, hire and train local researchers, conduct far (including a range of qualitative methods), and support action and advocacy. since the selected communities are diverse, the ways that the research unfolds will ·ary between communities. expected outcomes, such as the provision of a written report and resources, the establishment of a website for networking among the communities, and a video do.:umentary, are aimed at supporting the research participants, coalition members, and advisory conuniuces in their action efforts. p t (c) health & housing: assessing the impact of transitional housing for people living with hiv i aids currently, there is a dearth of available literature which examines supporrive housing for phas in the canadian context. using qualitative, one-on-one interviews we investigace the impact of transitional housing for phaswho have lived in the up to nine month long hastings program. our post<'r pr<·senta-t on will highlight research findings, as well as an examination of transitional housing and th<· imp;kt it has on the everyday lives of phas in canada. this research is one of two ground breaking undertakings within the province of ontario in which fife house is involved. p - (c) eating our way to justice: widening grassroots approaches to food security, the stop community food centre as a working model charles l.evkoe food hanks in north america have come co play a central role as the widespread response to growing rates of hunger. originally thought to be a short term-solution, over the last years, they have v poster sessions be · · · · d wi'thi'n society by filling the gaps in the social safety net while relieving govemcome mst tut ona ze . . . t f the ir responsibilities. dependent on corporate donations and sngmauzmg to users, food banks men so th' . · i i . are incapable of addressing the structural cause~ of ~u~ger. s pres~ntation w e~~ ore a ternanve approaches to addressing urban food security while bmldmg more sustamabl.e c~mmumt es. i:nrough the f t h st p community food centre, a toronto-based grassroots orgamzanon, a model is presented case e h'l k' b 'id · b that both responds to the emergency food needs of communities w e wor mg to. u ~ sustama le and just food system. termed, the community food centre model. (cfc), ~he s~op is worki?g to widen its approach to issues of food insecurity by combining respectful ~ rect service wit~ com~~mty ~evelop ment, social justice and environmental sustainability. through this approach, various critical discourses around hunger converge with different strategic and varied implications for a~ion. as a plac~-based organization, the stop is rooted within a geographical space and connected directly to a neighbourhood. through working to increase access to healthy food, it is active in maintaining people's dignity, building a strong and democratic community and educating for social change. connected to coalitions and alliances, the stop is also active in organizing across scales in connection with the global food justice movement. inner city shelter vicky stergiopoulos, carolyn dewa, katherine rouleau, shawn yoder, and lorne tugg introduction: in the city of toronto there are more than , hostel users each year, many with mental health and addiction issues. although shelters have responded in various ways to the health needs of their clients, evidence on the effectiveness of programs delivering mental health services to the home· less in canada has been scant. the objective of this community based research was to provide a forma· tive evaluation of a multi-agency collaborative care team providing comprehensive care for high needs clients at toronto's largest shelter for homeless men. methods: a logic model provided the framework for analysis. a chart review of clients referred over a nine month period was completed. demographic data were collected, and process and outcome indicators were identified for which data was obtained and analyzed. the two main outcome measures were mental status and housing status months after referral to the program. improvement or lack of improvement in mental status was established by chart review and team consensus. housing outcomes were determined by chart review and the hostel databases. results: of the clients referred % were single and % were unemployed. forty four percent had a psychiatric hospitalization within the previous two years. the prevalence of severe and persistent men· tal illness, alcohol and substance use disorders were %, % and % respectively. six months after referral to the program % of clients had improved mental status and % were housed. logistic regression controlling for the number of general practitioner and psychiatrist visits, presence of person· ality or substance use disorder and treatment non adherence identified two variables significantly associ· ated mental status improvement: the number of psychiatric visits (or, . ; % ci, . - . ) and treatment non adherence (or, . ; % ci, . - . ). the same two variables were associated with housing outcomes. history of forensic involvement, the presence of a personality or substance use disorder and the number of visits with a family physician were not significantly associated with either outcome. conclusions: despite the limitations in sample sire and study design, this study can yield useful informa· tion to program planners. our results suggest that strategies to improve treatment adherence and access to mental health specialists can improve outcomes for this population. although within primary care teams the appropriate collaborative care model for this population remains to be established, access to psychiatric follow up, in addition to psychiatric assessment services, may be an important component of a successful program. mount sinai hospital (msh) has become one of the pre-eminent hospitals in the world by contributing to the development of innovative approaches to effective health care and disease prevention. recently, the hospital has dedicated resources towards the development of a strategy aimed at enhancing the hospital's integration with its community partners. this approach will better serve the hospital in the current health care environment where local health integration networks have been struck to enhance and support local capacity to plan, coordinate and integrate service delivery. msh has had early success with developing partnerships. these alliances have been linked to programs serving key target populations with _estabhshe~. points of access to msh. recognizing the need to build upon these achievements to remain compe~mve, the hospital has developed a community integration strategy. at the forefront of this strategy is c.a.r.e (community advisory reference engine): the hospital's compendium of poster sessions v community partners. as a single point of access to community partner information, c.a.r.e. is more than a database. c.a.r.e. serves as the foundation for community-focused forecasting and a vehicle for inter and intra-organizational knowledge transfer. information gleaned from the catalog of community parmers can be used to prepare strategic, long-term partnership plans aimed at ensuring that a comprehensive array of services can be provided to the hospital community. c.a.r.e. also houses a permanent record of the hospital's alliances. this prevents administrative duplication and facilitates the formation of new alliances that best serve both the patient and the hospital. c.a.r.e. is not a stand-alone tool and is most powerful when combined with other aspects of the hospital's community integration strategy. it iscxpected that data from the hospital's community advisory committees and performance measurement department will also be stored alongside stakeholder details. this information can then be used to drive discussions at senior management and the board, ensuring congruence between stakeholder, patient and hospital objectives. the patient stands to benefit from this strategy. the unique, distinct point of reference to a wide array of community services provides case managers and discharge planners with the information they need to connect patients with appropriate community services. creating these linkages enhances the patient's capacity to convalesce in their homes or places of residence and fosters long-term connections to neighborhood supports. these connections can be used to assist with identifying patients' ongoing health care needs and potentially prevent readmission to hospital. introduction: recruiting high-risk drug users and sex workers for hiv-prevention research has often been hampered by limited access to hard to reach, socially stigmatized individuals. our recruitment effom have deployed ethnographic methodology to identify and target risk pockets. in particular, ethnographers have modeled their research on a street-outreach model, walking around with hiv-prevention materials and engaging in informal and structured conversations with local residents, and service providers, as well as self-identified drug users and sex workers. while such a methodology identifies people who feel comfortable engaging with outreach workers, it risks missing key connections with those who occupy the margins of even this marginal culture. methods: ethnographers formed a women's laundry group at a laundromat that had a central role as community switchboard and had previously functioned as a party location for the target population. the new manager helped the ethnographers invite women at high risk for hiv back into the space, this time as customers. during weekly laundry sessions, women initiated discussions about hiv-prevention, sexual health, and eventually, the vaccine research for which the center would be recruiting women. ra.its: the benefits of the group included reintroducing women to a familiar locale, this time as customers rather than unwelcome intruders; creating a span of time (wash and dry) to discuss issues important to me women and to gather data for future recruitment efforts; creating a location to meet women encountered during more traditional outreach research; establishing the site as a place for potential retention efforts; and supporting a local business. women who participated in the group completed a necessary household task while learning information that they could then bring back to the community, empowering them to be experts on hiv-prevention and vaccine research. some of these women now assist recruitment efforts. the challenges included keeping the group women-only, especially after lunch was provided, keeping the membership of the group focused on women at risk for hiv, and keeping the women in the group while they did their laundry. conclusion: public health educators and researchers can benefit from identifying alternate congregation sites within risk pockets to provide a comfortable space to discuss hiv prevention issues with high-risk community members. in our presentation, we will describe the context necessary for similar research, document the method's pitfalls and successes, and argue that the laundry group constitutes an ethical, respectful, community-based method for recruitment in an hiv-prevention vaccine trial. p - t (c) upgrading inner city infrastructure and services for improved environmental hygiene and health: a case of mirzapur in u.p. india madhusree mazumdar in urgency for agricultural and industrial progress to promote economic d.evelopment follo_wing independence, the government of india had neglected health promotion and given less emphasis on infrastructure to promote public health for enhanced human pro uct v_ity. ong wit r~p m astrucrure development, which has become essential if citie~ are to. act ~s harbmger.s of econ~nuc ~owth, especially after the adoption of the economic liberalization policy, importance _is a_lso ~emg g ve.n to foster environmental hygiene for preventive healthcare. the world health orga~ sat ~ is also trj:' ! g to help the government to build a lobby at the local level for the purpose by off~rmg to mrroduce_ its heal.thy city concept to improve public health conditions, so as to reduce th_e disease burden. this pape~ s a report of the efforts being made towards such a goal: the paper descr~bes ~ c~se study ?f ~ small city of india called mirzapur, located on the banks of the nver ganga, a ma or lifeline of india, m the eastern part of the state of uttar pradesh, where action for improvement began by building better sanitation and environmental infrastructure as per the ganga action plan, but continued with an effort to promote pre· ventive healthcare for overall social development through community participation in and around the city. asthma physician visits in toronto, canada tara burra, rahim moineddin, mohammad agha, and richard glazier introduction: air pollution and socio-economic status are both known to be associated with asthma in concentrated urban settings but little is known about the relationship between these factors. this study investigates socio-economic variation in ambulatory physician consultations for asthma and assesses possible effect modification of socio-economic status on the association between physician visits and ambient air pollution levels for children aged to and adults aged to in toronto, canada between and . methods: generalized additive models were used to estimate the adjusted relative risk of asthma physician visits associated with an interquartile range increase in sulphur dioxide, nitrogen dioxide, pm . , and ozone, respectively. results: a consistent socio-economic gradient in the number of physician visits was observed among children and adults and both sexes. positive associations between ambient concentrations of sul· phur dioxide, nitrogen dioxide and pm . and physician visits were observed across age and sex strata, whereas the associations with ozone were negative. the relative risk estimates for the low socio-«onomic group were not significantly greater than those for the high socio-economic group. conclusions: these findings suggest that increased ambulatory physician visits represent another component of the public health impact of exposure to urban air pollution. further, these results did not identify an age, sex, or socio-economic subgroup in which the association between physician visits and air pollution was significantly stronger than in any other population subgroup. eco-life-center (ela) in albania supports a holistic approach to justice, recognizing the environ· mental justice, social justice and economic justice depend upon and support each other. low income cit· izens and minorities suffer disproportionately from environmental hazards in the workplace, at home, and in their communities. inadequate laws, lax enforcement of existing environmental regulations, and ~ea.k penalties for infractions undermine environmental protection. in the last decade, the environmental ust ce m~ve~ent in tirana metropolis has provided a framework for identifying and exposing the links ~tween irrational development practices, disproportionate siting of toxic facilities, economic depres· s on, and a diminished quality of life in low-income communities and communities of color. the envi· ~onmental justice agenda has always been rooted in economic, racial, and social justice. tirana and the issues su.rroun~ing brow~fields redevelopment are crucial points of advocacy and activism for creating ~ubstantia~ social chan~~ m low-income communities and communities of color. we engaging intensively m prevcnnng co'.' mumnes, especially low income or minority communities, from being coerced by gov· ernmenta~ age_nc es or companies into siting hazardous materials, or accepting environmentally hazard· ous_ practices m order to create jobs. although environmental regulations do now exist to address the environmental, health, and social impacts of undesirable land uses, these regulations are difficult to poster sessions v enforce because many of these sites have been toxic-ridden for many years and investigation and cleanup of these sites can be expensive. removing health risks must be the main priority of all brown fields action plans. environmental health hazards are disproportionately concentrated in low-income communities of color. policy requirements and enforcement mechanisms to safeguard environmental health should be strengthened for all brownfields projects located in these communities. if sites are potentially endangering the health of the community, all efforts should be made for site remediation to be carried out to the highest cleanup standards possible towards the removal of this risk. the assurance of the health of the community should take precedence over any other benefits, economic or otherwise, expected to result from brownfields redevelopment. it's important to require from companies to observe a "good neighbor" policy that includes on-site visitations by a community watchdog committee, and the appointment of a neighborhood environmentalist to their board of directors in accordance with the environmental principles. vancouver - michael buzzelli, jason su, and nhu le this is the second paper of research programme concerned with the geographical patterning of environmental and population health at the urban neighbourhood scale. based on the vancouver metropolitan region, the aim is to better understand the role of neighbourhoods as epidemiological spaces where environmental and social characteristics combine as health processes and outcomes at the community and individual levels. this paper builds a cohort of commensurate neighbourhoods across all six censuses periods from to , assembles neighbourhood air pollution data (several criterion/health effects pollutants), and providing an analysis to demonstrate how air pollution systematically and consistently maps onto neighbourhood socioeconomic markers, in this case low education and lone-parent families. we conclude with a discussion of how the neighbourhood cohort can be further developed to address emergent priorities in the population and environmental health literatures, namely the need for temporally matched data, a lifecourse approach, and analyses that control for spatial scale effects. solid waste management and environment in mumbai (india) by uttam jakoji sonkamble and bairam paswan abstract: mumbi is the individual financial capital of india. the population of greater mumbai is , , and sq. km. area. the density of population , per sq. km. the dayto-day administration and rendering of public services within gr. mumbai is provided by the brihan mumbai mahanagar palika (mumbai corporation of gr. mumbai) that is a body of elected councilors on a -year team. mumcial corporation provides varies conservancy services such as street sweeping, collection of solid waste, removal and transportation, disposal of solid waste, disposal of dead bodies of animals, construction, maintance and cleaning of urinals and public sanitary conveniences. the solid waste becoming complicated due to increase in unplanned urbanization and industrialization, the environment has deteriorated significantly due to inter, intra and international migration stream to mumbai. the volume of inter state migration to mumbai is considerably high i.e. . lakh and international migrant . lakh have migrated to mumbai. present paper gives the view on solid waste management and its implications to environment and health. pollution from a wide varity of emission, such as from automobiles and industrial activities, has reached critical level in mumbai, causing respiratory, ocular, water born diseases and other health problems. sources of generation of waste are -household waste, commercial waste, institutional waste, street sweeping, silt removed from drain/nallah/cleanings. disposal of solid waste in gr. mumbai done under incineration . processing to produce organic manure. . vermi-composting . landfill the study shows that the quantity of waste disposal of through processing and conversion to organic ~anure is about - m.t. per day. the processing is done by a private agency m/s excel industries ltd. who had set up a plant at the chincholi dumping ground in western mumbai for this purpose. the corporation is also disposal a plant of its waste mainly market waste through the environment friendly, natural pro-ces~ known as vermi-composing about m.t. of market waste is disposed of in this manner at the various sites. there are four land fill sites are available and percent of the waste matter generated m mumbai is disposed of through landfill. continuous flow of migrant and increa~e in slum population is a complex barrier in the solid waste management whenever community pamc pat on work strongly than only we can achieved eco-friendly environment in mumbai. persons exposed to residential craffic have elevated races of respiratory morbidity an~ ~ortality. since poverty is an important determinant of ill-health, some h~ve argued that t~es~ assoc at ons may relate to che lower socioeconomic status of those living along ma or roads. our ob ect ve was to evaluate the association between traffic intensity at home and hospital admissions for respiratory diagnoses among montreal residents older than years. morning peak traffic estimates from the emmej montreal traffic model (motrem ) were used as an indicator of exposure to road traffic outside the homes of those hospitalised. the influence of socioeconomic status on the relationship between traffic intensity and hospital admissions for respiratory diagnoses was explored through assessment of confounding by lodging value, expressed as the dollar average over road segments. this indicator of socioeconomic status, as calculated from the montreal property assessment database, is available at a finer geographic scale than socioeconomic information accessible from the canadian census. there was an inverse relationship between traffic intensity estimates and lodging values for those hospitalised (rho - . , p vehicles during che hour morning peak), even after adjustment for lodging value (crude or . , cl % . - . ; adjusted or . , cl % . - . ). in montreal, elderly persons living along major roads are at higher risk of being hospitalised for respiratory illnesses, which appears not simply to reflect the fact that those living along major roads are at relative economic disadvantage. the paper argues that human beings ought to be at the centre of the concern for sustainable development. while acknowledging the importance of protecting natural resources and the ecosystem in order to secure long term global sustainability, the paper maintain that the proper starting point in the quest for urban sustainability in africa is the 'brown agenda' to improve che living and working environment of che people, especially che urban poor who face a more immediate environmental threat to their health and well-being. as the un-habitat has rightly observed, it is absolutely essential "to ensure that all people have a sufficient stake in the present to motivate them to take part in the struggle to secure the future for humanity.~ the human development approach calls for rethinking and broadening the narrow technical focus of conventional town planning and urban management in order to incorporate the emerging new ideas and principles of urban health and sustainability. i will examine how cities in sub-saharan africa have developed over the last fifty years; the extent to which government policies and programmes have facilitated or constrained urban growth, and the strategies needed to achieve better functioning, safer and more inclusive cities. in this regard i will explore insights from the united nations conferences of the s, especially local agenda of the rio summit, and the istanbul declaration/habitat agenda, paying particular attention to the principles of enablement, decentralization and partnership canvassed by these movements. also, i will consider the contributions of the various global initiatives especially the cities alliance for cities without slums sponsored by the world bank and other partners; che sustainable cities programme, the global campaigns for good governance and for secure tenure canvassed by unhabit at, the healthy cities programme promoted by who, and so on. the concluding section will reflect on the future of the african city; what form it will take, and how to bring about the changes needed to make the cities healthier, more productive and equitable, and better able to meet people's needs. heather jones-otazo, john clarke, donald cole, and miriam diamond urban areas, as centers of population and resource consumption, have elevated emissions and concentrations of a wide range of chemical contaminants. we have developed a modeling framework in which we first ~stimate the emissions and transport of contaminants in a city and second, use these estimates along with measured contaminant concentrations in food, to estimate the potential health risk posed by these che.micals. the latter is accomplished using risk assessment. we applied our modeling framework to consider two groups of chemical contaminants, polycyclic aromatic hydrocarbons (pah) a.nd the flame re~ardants polybrominated diphenyl ethers (pbde). pah originate from vehicles and stationary combustion sources. ~veral pah are potent carcinogens and some compounds also cause noncancer effects. pbdes are additive flame retardants used in polyurethane foams (e.g., car seats, furniture) fer sessions v and cl~ equipm~nt (e.g., compute~~· televisio~s). two out of three pbdes formulations are being voluntarily phased by mdustry due to rmng levels m human tissues and their world-wide distribution. pbdes have been .related to adv.erse neurological, developmental and reproductive effects in laboratory ijlimals. we apphed our modelmg framework to the city of toronto where we considered the southcattral area of by km that has a population of . million. for pah, local vehicle traffic and area sources contribute at least half of total pah in toronto. local contributions to pbdes range from - %, depending on the assumptions made. air concentrations of both compounds are about times higher downtown than km north of toronto. although measured pah concentrations in food date to the s, we estimate that the greatest exposure and contribution to lifetime cancer risk comes from ingestion of infant formula, which is consistent with toxicological evidence. the next greatest exposure and cancer risk are attributable to eating animal products (e.g. milk, eggs, fish). breathing downtown air contributes an additional percent to one's lifetime cancer risk. eating vegetables from a home garden localed downtown contributes negligibly to exposure and risk. for pbdes, the greatest lifetime exposure comes through breast milk (we did not have data for infant formula), followed by ingestion of dust by the toddler and infant. these results suggest strategies to mitigate exposure and health risk. p - (a) immigration and socioeconomic inequalities in cervical cancer screening in toronto, canada aisha lofters, rahim moineddin, maria creatore, mohammad agha, and richard glazier llltroduction: pap smears are recommended for cervical cancer screening from the onset of sexual activity to age . socioeconomic and ethnoracial gradients in self-reported cervical cancer screening have been documented in north america but there have been few direct measures of pap smear use among immigrants or other socially disadvantaged groups. our purpose was to investigate whether immigration and socioeconomic factors are related to cervical cancer screening in toronto, canada. methods: pap smears were identified using fee codes and laboratory codes in ontario physician service claims (ohip) for three years starting in for women age - and - . all women with any health system contact during the three years were used as the denominator. social and economic factors were derived from the canadian census for census tracts and divided into quintiles of roughly equal population. recent registrants, over % of whom are expected to be recent immigrants to canada, were identified as women who first registered for health coverage in ontario after january , . results: among , women age - and , women age - , . % and . %, rtspcctively, had pap smears within three years. low income, low education, recent immigration, visible minority and non-english language were all associated with lower rates (least advantaged quintile:most advantaged quintile rate ratios were . , . , . , . , . , respectively, p < . for all). similar gradients were found in both age groups. recent registrants comprised . % of women and had mm;h lower pap smear rates than non-recent registrants ( . % versus . % for women age - and . % versus . % for women age - ). conclnsions: pap smear rates in toronto fall well below those dictated by evidence-based practice. at the area level, immigration, visible minority, language and socioeconomic characteristics are associated with pap smear rates. recent registrants, representing a largely immigrant group, have particularly low rates. efforts to improve coverage of cervical cancer screening need to be directed to all ~omen, their providers and the health system but with special emphasis on women who recently arrived m ontario and those with social and economic disadvantage. challeges faced: a) most of the resources are now being ~pent in ~reventing the sprea.d of hiv/ aids and maintaining the lives of those already affected. b) skilled medical ~rs~nal are dymg under· mining the capacity to provide the required health care services. ~) th.e comphcat o~s of hiv/aids has complicated the treatment of other diseases e.g. tbs d) the ep dem c has led. to mcrease number of h n requiring care and support. this has further stretched the resources available for health care. orp a s d db . . i methods used on our research: . a simple community survey con ucte y our orgamzat on vo · unteers in three urban centres members of the community, workers and health care prov~ders were interviewed ... . meeting/discussions were organized in hospitals, commun.ity centre a~d with government officials ... . written questionnaires to health workers, doctors and pohcy makers m th.e health sectors. lessors learning: • the biggest-health bigger-go towards hiv/aids prevention • aids are spreading faster in those families which are poor and without education. •women are the most affected. •all health facilities are usually overcrowded with hiv/aids patients. actions needed:• community education oh how to prevent the spread of hiv/aids • hiv/aids testing need to be encouraged to detect early infections for proper medical cover. • people to eat healthy • people should avoid drugs. implications of our research: community members and civic society-introduction of home based care programs to take care of the sick who cannot get a space in the overcrowded public hospitals. prl-v a te sector private sector has established programs to support and care for the staff already affected. government provision of support to care-givers, in terms of resources and finances. training more health workers. introduction: australian prisons contain in excess of , prisoners. as in most other western countries, reliance on 'deprivation of liberty' is increasing. prisoner numbers are increasing at % per annum; incarceration of women has doubled in the last ten years. the impacts on the community are great - % of children have a parent in custody before their th birthday. for aboriginal communities, the harm is greater -aboriginal and/or torres strait islanders are incarcerated at a rate ten times higher than other australians. % of their children have a parent in custody before their th birthday. australian prisons operate under state and territory jurisdictions, there being no federal prison system. eight independent health systems, supporting the eight custodial systems, have evolved. this variability provides an unique opportunity to assess the capacity of these health providers in addressing the very high service needs of prisoners. results: five models of health service provision are identified -four of which operate in one form or another in australia: • provided by the custodial authority (queensland and western australia)• pro· vided by the health ministry through a secondary agent (south australia, the australian capital territory and tasmania) • provided through tendered contract by a private organization (victoria and northern territory) • provided by an independent health authority (new south wales) • (provided by medics as an integral component of the custodial enterprise) since the model of the independent health authority has developed in new south wales. the health needs of the prisoner population have been quantified, and attempts are being made to quantify specific health risks /benefits of incarceration. specific enquiry has been conducted into prisoner attitudes to their health care, including issues such as client information confidentiality and access to health services. specific reference will be made to: • two inmate health surveys • two inmate access surveys, and • two service demand studies. conclusions: the model of care provision, with legislative, ethical, funding and operational independence would seem provide the best opportunity to define and then respond to the health needs of prisoners. this model is being adopted in the united kingdom. better health outcomes in this high-risk group, could translate into healthier families and their communities. p - (a) lnregrated ethnic-specific health care systems: their development and role in increasing access to and quality of care for marginalized ethnic minorities joshua yang introduction: changing demographics in urban areas globally have resulted in urban health systems that are racially and ethnically homogenous relative to the patient populations they aim to serve. the resultant disparities in access to and quality of health care experienced by ethnic minority groups have been addressed by short-term, instirutional level strategies. noticeably absent, however, have been structural approaches to reducing culturally-rooted disparities in health care. the development of ethnic-specific h~alth car~ systems i~ a structural, long-term approach to reducing barriers to quality health care for eth· me mmonty populations. methods: this work is based on a qualitative study on the health care experiences of san francisco chinatown in the united states, an ethnic community with a model ethnic-specific health care infrastrucrure. using snowball sampling, interviews were conducted with key stakeholders and archival research was conducted to trace and model the developmental process that led to the current ethnic-specific health care system available to the chinese in san francisco. grounded theory was the methodology ijltd to analysis of qualitative data. the result of the study is four-stage developmental model of ethnic-specific health infrastrueture development that emerged from the data. the first stage of development is the creation of the human capital resources needed for an ethnic-specific health infrastructure, with emphasis on a bilingual and bicultural health care workforce. the second stage is the effective organization of health care resources for maximal access by constituents. the third is the strengthening and stability of those institutional forms through increased organizational capacity. integration of the ethnic-specific health care system into the mainstream health care infrastructure is the final stage of development for an ethnic-specific infrastructure. conclusion: integrated ethnic-specific health care systems are an effective, long-term strategy to address the linguistic and cultural barriers that are being faced by the spectrum of ethnic populations in urban areas, acting as culturally appropriate points of access to the mainstream health care system. the model presented is a roadmap to empower ethnic communities to act on the constraints of their health and political environments to improve their health care experiences. at a policy level, ethnic-specific health care organizations are an effective long-term strategy to increase access to care and improve qualiiy of care for marginalized ethnic groups. each stage of the model serves as a target area for policy interventions to address the access and care issues faced by culturally and linguistically diverse populations. users in baltimore md: - noya galai, gregory lucas, peter o'driscoll, david celentano, david vlahov, gregory kirk, and shruti mehta introduction: frequent use of emergency rooms (er) and hospitalizations among injection drug users (idus) has been reported and has often been attributed to lack of access to primary health care. however, there is little longitudinal data which examine health care utilization over individual drug use careers. we examined factors associated with hospitalizations, er and outpatient (op) visits among idus over years of follow-up. methods: idus were recruited through community outreach into the aids link to lntravenous experience (alive) study and followed semi-annually. , who had at least follow-up visits were included in this analysis. outcomes were self-reported episodes of hospitalizations and er/op visits in the prior six months. poisson regression was used accounting for intra-person correlation with generalized estimation equations. hits: at enrollment, % were male, % were african-american, % were hiv positive, median age was years, and median duration of drug use was years. over a total of , visits, mean individual rates of utilization were per person years (py) for hospitalizations and per py for er/op visits. adjusting for age and duration of drug use, factors significantly associated with higher rates of hospitalization included hiv infection (relative incidence [ri(, . ), female gender (ri, . ), homelessness (ri, . ), as well as not being employed, injecting at least daily, snorting heroin, havmg a regular source of health care, having health insurance and being in methadone mainte.nance treatment (mmt). similar associations were observed for er/op visits except for mmt which was not associated with er/op visits. additional factors associated with lower er/op visits were use of alcohol, crack, injecting at least daily and trading sex for drugs. % of the cohort accounted for % of total er/op visits, while % of the cohort never reported an op visit during follow-up. . . . lgbt) populations. we hypothesized that prov dmg .appomtments .for p~t ~nts w thm hours would ensure timely care, increase patient satisfaction, and improve practice eff c ency. further, we anticipated that the greatest change would occur amongst our homeless patients.. . methods: we tested an experimental introduction of advanced access scheduling (usmg a hour rule) in the primary care medical clinic. we tracked variables inclu~ing waiting ti~e fo~ next available appointment; number of patients seen; and no-show rates, for an eight week penod pnor to and post introduction of the new scheduling system. both patient and provider satisfaction were assessed using a brief survey ( questions rated on a -pt scale). results and conclusion: preliminary analyses demonstrated shorter waiting times for appointments across the clinic, decreased no-show rates, and increased clinic capacity. introduction of the advanced access scheduling also increased both patient and provider satisfaction. the new scheduling was initiated in july . quantitative analyses to measure initial and sustained changes, and to look at differential responses across populations within our clinic, are currently underway. introduction: there are three recognized approaches to linking socio-economic factors and health: use of census data, gis-based measures of accessibility/availability, and resident self-reported opinion on neighborhood conditions. this research project is primarily concerned with residents' views about their neighborhoods, identifying problems, and proposing policy changes to address them. the other two techniques will be used in future research to build a more comprehensive image of neighborhood depri· vation and health. methods: a telephone survey of london, ontario residents is currently being conducted to assess: a) community resource availability, quality, access and use, b) participation in neighborhood activities, c) perceived quality of neighborhood, d) neighborhood problems, and e) neighborhood cohesion. the survey instrument is composed of indices and scales previously validated and adapted to reflect london specifically. thirty city planning districts are used to define neighborhoods. the sample size for each neighborhood reflects the size of the planning district. responses will be compared within and across neighborhoods. data will be linked with census information to study variation across socio-eco· nomic and demographic groups. linear and gis-based methods will be used for analysis. preliminary results: the survey follows a qualitative study providing a first look at how experts involved in community resource planning and administration and city residents perceive the availability, accessibility, and quality of community resources linked to neighborhood health and wellbeing, and what are the most immediate needs that should be addressed. key-informant interviews and focus groups were used. the survey was pre-tested to ensure that the language and content reflects real experiences of city residents. the qualitative research confirmed our hypothesis that planning districts are an acceptable surrogate for neighborhood, and that the language and content of the survey is appropriate for imple· mentation in london. scales and indices showed good to excellent reliability and validity during the pre· test (cronbach's alpha from . - . ). preliminary results of the survey will be detailed at the conference. conclusions: this study will help assess where community resources are lacking or need improve· ment, thus contributing to a more effective allocation of public funds. it is also hypothesized that engaged neighborhoods with a well-developed sense of community are more likely to respond to health programs and interventions. it is hoped that this study will allow london residents to better understand the needs and problems of their neighborhoods and provide a research foundation to support local understandmg of community improvement with the goal of promoting healthy neighborhoods. p - (a) hiv positive in new york city and no outpatient care: who and why? hannah wolfe and victoria sharp introduction: there are approximately million hiv positive individuals living in the united sta!es. about. % of these know their hiy status and are enrolled in outpatient care. of the remaining yo, approx~mately half do not know their status; the other group frequently know their status but are not enrolled m any .sys~em of outpatient care. this group primarily accesses care through emergency departments. when md cated, they are admitted to hospitals, receive acute care services and then, upon poster sessions v di 'harge, disappear from the health care system until a new crisis occurs, when they return to the emergency department. as a large urban hiv center, caring for over individuals with hiv we have an active inpatient service ".'ith appr~xi~.ately discharges annually. we decided to survey our inpatients to better charactenze those md v duals who were not enrolled in any system of outpatient care. results: % of inpatients were not enrolled in regular outpatient care: % at roosevelt hospital and % at st.luke\'s hospital. substance abuse and homelessness were highly prevalent in the cohort of patients not enrolled in regular outpatient care. % of patients not in care (vs. % of those in care) were deemed in need of substance use treatment by the inpatient social worker. % of those not in care were homeless (vs. % of those in care.) patients not in care did not differ significantly from those in me in terms of age, race, or gender. patients not in care were asked "why not:" the two most frequent responses were: "i haven't really been sick before" and "i'd rather not think about my health. conclusions: this study suggests that there is an opportunity to engage these patients during their stay on the inpatient units and attempt to enroll them in outpatient care. simple referral to an hiv clinic is insufficient, particularly given the burden of homelessness and substance use in this population. efforts are currently underway to design an intervention to focus efforts on this group of patients. p .q (a) healthcare availability and accessibility in an urban area: the case of ibadan city, nigeria in oder to cater for the healthcare need of the populace, for many years after nigeria's politicl independence, empphasis was laid on the construction of teaching, general, and specialist hospital all of which were located in the urban centres. the realisation of the inadequacies of this approach in adequately meeting the healthcare needs of the people made the country to change and adopt the primary health care (phc) system in . the primary health care system which is in line with the alma ata declaration of of , wsa aimed at making health care available to as many people as possible on the basis of of equity and social justice. thus, close to two decades, nigeria has operated primary health care system as a strategy for providing health care for rural and urban dwellers. this study focusing on urban area, examimes the availabilty and accessibility of health care in one of nigeria's urban centre, ibadan city to be specific. this is done within the contest of the country's national heath policy of which pimary health care is the main thrust. the study also offers necessary suggestion for policy consideration. in spite of the accessibility to services provided by educated and trained midwifes in many parts of fars province (iran) there are still some deliveries conducted by untrained traditional birth attendants in rural parts of the province. as a result, a considerable proportion of deliveries are conducted under a higher risk due to unauthorised and uneducated attendants. this study has conducted to reveal the pro· portion of deliveries with un-authorized attendants and some spatial and social factors affecting the selection of delivery attendants. method: this study using a case control design compared some potentially effective parameters indud· ing: spatial, social and educational factors of mothers with deliveries attended by traditional midwifes (n= ) with those assisted by educated and trained midwifes (n= ). the mothers interviewed in our study were selected from rural areas using a cluster sampling method considering each village as a cluster. results: more than % of deliveries in the rural area were assisted by traditional midwifes. there are significant direct relationship between asking a traditional birth attendant for delivery and mother age, the number of previous deliveries and distance to a health facility provided for delivery. significant inverse relationships were found between mother's education and ability to use a vehicle to get to the facilities. conclusion: despite the accessibility of mothers to educated birth attendants and health facilities (according to the government health standards), some mothers still tend to ask traditional birth attendants for help. this is partly because of unrealistic definition of accessibility. the other considerable point is the preference of the traditional attendants for older and less educated mothers showing the necessity of changing theirs knowledge and attitude to understand the risks of deliveries attended by traditional and un-educated midwifes. p - (a) identification and optimization of service patterns provided by assertive community treatment teams in a major urban setting: preliminary findings &om toronto, canada jonathan weyman, peter gozdyra, margaret gehrs, daniela sota, and richard glazier objective: assertive community treatment (act) teams are financed by the ontario ministry of health and long-term care (mohltc) and are mandated to provide treatment, rehabilitation and support services in the community to people with severe and persistent mental illness. there are such teams located in various regions across the city of toronto conducting home visits - times per week to each of their approximately respective clients. each team consists of multidisciplinary health professionals who assist clients to identify their needs, establish goals and work toward them. due to complex referral patterns, the need for service continuity and the locations of supportive housing, clients of any one team are often found scattered across the city which increases home visit travel times and decreases efficiency of service provision. this project examines the locations of clients in relation to the home bases of all act teams and identifies options for overcoming the geographical challenges which arise in a large urban setting. methods: using geographic information systems (gis) we geocoded all client and act agency addresses and depicted them on location maps. at a later stage using spatial methods of network analysis we plan to calculate average travel rimes for each act team, propose optimization of catchment areas and assess potential travel time savings. resnlts: initial results show a substantial scattering of clients from several act teams and substan· rial overlap of visit travel routes for most teams. conclusions: reallocation of catchment areas and optimization of act teams' travel patterns should lead to substantial savings in travel times, increased service efficiency and better utilization of resourc_~· ~e l'<!tenri~i modifications to catchment areas must be conducted with appropriate attention to specific clients servtce needs, service continuity and applicable regulations by the mohl tc. venice lido is a popular island within and outside italy because it hosts the international cinema festival yearly. only few people remember the island for its hospital, which, in the fifties, was one of the most important hospitals in italy and in europe, being a modern center for wind-, sun-and thermal-therapy. since the sixties, its fame became to drop away, since its structure was no longer adequate for the evolving medicine science. at the end of the seventies all the wards were moved into a new big building in the same area. at present the hospital is made up by about forty 'pavilions' (mostly partially used or empty) and a big building, disseminated in a hectares area, on the sea front, on the m long beach. the aim of my research is to suggest a realistic solution, sustainable on the functional use of the area according to basic local needs and economically realizable. i used a philological and multi-disciplinary method, more in detail: -from historical documents, i found what was the very first call of the property and how it adapted to the needs of the demographic development and the sanitary supply over time; -by contacting some operators from different fields, i realized which functions were suitable to the buildings in existence, to the population's needs and to the present sanitary supply. moreover the planning idea considers: -the debate going on between local people who strongly want to preserve the property, and die ones who want to renew it by different new opportunities; and -the regional sanitary politics, aiming at rationalizing the regional hospitals dislocation, and the budget needs. this plan analyzes and proposes some new alternative solutions to satisfy different needs. the different activities will be dealt out and the environmental fall will be limited as much as possible. after having analyzed its basic call, considered its environmental peculiarities and its position, verified the emerging needs of the local population, the plan proposes different activities: the hospital; the social-rehabilitation center; the elderly house; the thermal center; the residential center; and other activities. such a plan wants to share in the solution of a basic problem by giving architectonic and functional dignity to an historical completely degraded area and by starting again a social-economical broken off process, by bringing in venice lido some fresh necessary elements for its so wished new throw. p - (c) dilemma of free health care in spokane, wa david bunting introduction: the paper reports on the activities of project access spokane [pas], a physician sponsored initiative to provide uncompensated health care to low income, uninsured residents of spokane county wa. program providers included all county hospitals, over physicians, other medical professionals, and specialized clinics. each prescription requires only a $ co-payment. sponsored and administered by the county medical society, pas is funded by local and national foundations, private corporations, municipalities, civic organizations and individuals. method: the paper is based on a first year assessment report funded by pas, using hcfa [health care financing administration] insurance claim data documenting utilization rates, disease categories and donated charge information and patient cares [centralized applications, referrals and enrollment status) data. results: while essentially free for enrollees, the program involved real costs. an administrative organization to refer over patients to any of over providers had to be developed and staffed, using both paid and unpaid personnel. methods to identify potential patients and veri.fy eligibility. had to ~devised. patient appointments and transportation had to be scheduled and monitored. pu~hc relanons, provider solicitations and fundraising activities were continuous. information requirements regarding program operation were also significant. data reporting the volume. ~nd value of dona~ed medical services were necessary to demonstrate accomplishments and attr~ct addmon~l support. providers required assurances their contributions were both significant and eqmtable. funding sources sought evidence that their support had important consequences. however, generating this ~~ta proved difficult. many providers failed to submit appropriate insurance claims forms because .of a~dmonal donated effort and administrative cost, thereby not only reducing their own apparent conmbut ons but also the overall significance of the program. conclusions: during its initial year, the estimated cost to deliver free health care was ~bout per enrollee. the lesson is that without an elaborate administrative structure and record keeping s.yst~~· efforts to provide free health care probably will fail. eligible enrollees c~n not be ~parated from in~hgi ble ones, care will not be accessed or delivered in an efficient manner, neither fundmg nor ~upport "". be offered without evidence of tangible benefits, and providers will withdraw if they perceive mequ table tteannent. v p - s (c) mobility in prostitution and the impact of health therese van der helm and henk sulman poster sessions introduction: many of the estimated . commer~ial ~ex wor~ers (c~w)in a'.' ~terdam ~~me from developing countries and eastern europe. to gain ins~ght mto their workmg and_ hvmg condinons the intermediary project (ip) at the municipal health serv ~e _contacts these women via ?utreach work on regular basis. since the new brothel law in october s ~troduc~d, ~sw ~rom outside the eu and who have no dutch residence permit are not allowed to work m prost tut n. smee then, many of these csw therefore have gone "underground." the consequences of the new law in the netherlands will be discussed with regard to the accessibility of csw and their risk for stl/hiv acquisition and unplanned pregnancies. methods: topics during outreach work are the interventions to increase the knowledge of safe sex and birth control for csw. written information is handed out in relevant languages and with addresses of health and social services. in conversations with the women, it appeared that many are not aware of these services. to provide easier access to health care for women, staff of the ip carries out free sti control csw working places, in windows brothels and sex houses. also, women are offered vaccination against hepatitis b (hbv). results: from january till july we approached csw for first contact. one third was dutch; others were from developing countries, other eu countries and eastern europe. sti consul· rations were done among non-iv drug using sex workers, of whom % was dutch. of these, % was diagnosed with syphilis, % with gonorrhea, and % with chlamydia. of women tested for hiv, none were infected. due to the high turnover of csw in .brothels, most wnmen were tested only once. among csw tested for hbv -of whom one third is dutch - % had antibodies for hbv, were carrier of hbv, most of whom came from hbv endemic areas. conclusions: sti control and hbv vaccination in brothels is an important support in health care. our findings suggest that csw do not play an important role in the transmission of sti. many csw are highly mobile and often not aware of the existing health and social services. continuous outreach is important to remain in contact with this mobile population. regulations in the new brothel law should not hamper contacts with (illegal) csw. heart disease (cho) is projected to become the leading cause of death. studies conducted in europe and the united states have proven a higher rate of cho in south asians who have migrated from south asia, most notably india, pakistan and bangladesh. approximately % of all heart attacks among south asian men occur under the age of ; % of them occur under the age of -unheard of in any other population. associated risk factors such as diabetes, high blood pressure and cholesterol are also com· mon in this group. the population of south asians residing in nyc has more than doubled over the past decade to over , , the majority being young, working-class and with limited health care access. many south asian men are employed as taxi drivers ( out of nyc taxi drivers are from south asial, working daily hour plus shifts. methods: acknowledging that this vulnerable, at-risk group was unavailable for outreach through conventional venues, three of the hospitals of the new york city health and hospital corporation, (elmhurst, queens and bellevue) conducted a one day outreach effort at nyc's jfk international air· ~rt's taxi holdin~ ar~a, ~here over one thousand taxis regularly assemble. bringing an outreach event directly to the taxi dnvers workplace, a tent was set up where cardiovascular-related health screenings, in~luding bl~ pressure, sugar, cholesterol, body mass index (bmi), were provided. results were shared with and explamed to the drivers and each participant received a south asian health education brochure. a total of taxi drivers who identified as south asian were involved. rau/ts: participants were all male, ranging from to years; mean age, . . screenings revealed % hypertensive; % had cholesterols over ; % blood glucose over ; % had a bmi greater than . conc~on: a unique outreach activity, adapting to logistical, occupational limitations, is pre· se~ted. on-site f~back and explanation of results, reiterating and reinforcing the concern that south asia~. men are at mcreased danger for early coronary heart disease, and the dissemination of a culturally sensmve and r~levant brochure, may heighten awareness of prevailing cardiac risk factors in this immi· grant community. p - (c) the community-hospital integration program framework: community-hospital panoenhips to improve the population's health john stevenson, richard blickstead, ann-marie marcolin, and sandi kendal v introduction: st. josephs health centre is a catholic community teaching hospital located in the heart of southwest toronto. st. joseph\'s was founded from a community-expressed need for hospital services, and since then has stayed committed to fostering a healthy community through collaboration and parmership. st. joseph's has developed an innovative model, the community-hospital integration program (chip), to strengthen st. joseph's partnerships with community stakeholders, and facilitates the building of links between community needs, service provision, and public policy outcomes to improve the health and wellness of the diverse neighbourhoods they together serve. methods: development of the chip framework st. joseph's health centre developed the chip framework through a multidisciplinary approach that included extensive international literature reviews, consultations, and key informant interviews with community service agencies and academics. to ensure active community voice, st. joseph's has hosted a number of community consultations including a community outreach forum attended by over ninety representatives from community partners. results: the chip framework the chip framework aims to improve the health and wellness of the urban communities served by st. josephs health centre through four intersecting pillars: • raising community voices provides an infrastructure and process that supports community stakeholder input into health care service planning, decision-making, and delivery by the hospital and across the continuum of care; • sharing reciprocal capacity promotes healthy communities through the sharing of our intellectual and physical capacity with our community partners; • cultivating integration initiatives facilitates vertical, horizontal, and intersectoral integration initiatives in support of community-identified needs and gaps; and • facilitating healthy exchange develops best practices in community integration through community-based research, and facilitates community voice in informing public policy. the chip framework drives the complex inter-relationships between community-hospital engagement, reciprocal capacity-building, integration initiatives, and community-based research and evaluation, to create an interconnected network of health care services. the fluidity and simplicity of this framework, and its dedication to balancing community needs and hospital mandate, posits the st. josephs health centre's chip model as an integral component in building healthy and thriving communities. p - (c) home based care promotion: improving acess to quality services and livelihood in the face of aids home based care is a service provided to persons affected/living with hiv/aids, a menu of care/support services at home/community. it is a prominent alternative approach. in uganda, hospital bed ocupacny is high, patient health care worker ratio deteriorating. empowering communities offers solutions to the problems; adressing cost, effectiveness of care. hiv/aids demands changes in attitudes, behaviour, approaches which is enhanced in home/community settings. for example art requires high levels of adherecnce, which medical workers have vety little opportunity to enforce. it also demands other support mechanisims in terms of nutrition, personal displine, etc which work best in stigma free environments. hence the relevance of home based care. this paper highlights the gaps that call for increased action in terms of home based care, examples of whre it has worked key challenges and recommendations for the future. p - (c) health care for one ... health care for alli katharina kovacs burns introduction: at the surface, it appears that every person in canada _has. ~ccess to a publicly funded health care system. those living in urban centers should have the best ava l~b hty, chmce, and access to a variety of health care services because of the distribution of health care services, fac lmes, and health professionals in concentrated in urban centers. this is not true for everyone -people with low income or who are homeless experience the challenges of social exclusion and being marginalized: there are many factors at play making it difficult for the latter group of people to access health care. service they need,.when they need them. health care is not as accessible or inclusive as intended. the quesuon to be explore.cl ~: if health care is available and accessible to one person, what makes it not available to all people? the ~ gmfic~nce of having marginalized people accessing health care and other services includes e~hanced quality of hfe and decreased risks associated with being homeless, and cost savings in ion~ ter~ w rh acute health care. methodology: community-based participatory research is applied m a case study on health care access and challenges experienced by low income and homeless people in one urban centre, edmonton, edmonton, and their challenges. the data is being gathered and ana_lyzed usmg basic m x~d methods. results: the results will focus on how services can be more mtegrated and accessible to all people with low income and who are homeless. there will also be discussion about specific perceptions of not only the service providers but also of people with low income an~ who are homeless~ and vario~s decision makers. the results will be compared to the literature regardmg health care services access mother urban centers in canada and elsewhere. conclusions: recommendations will need to address social exclusion and other factors which can make health care and other services more available to all people in the community. the implications for health care will also be discussed. additional information will be gathered in the next phases of the study to develop a community services access model. p - (c) availability and access exemplified: a case study beth hayhoe and ruth ewert introduction: access to health care in canada requires either the correct documentation or money. street youth have neither. in addition, health services in canada are designed by adults for adults. youth in general are often wary of having trust in adults with respect to their health concerns and frequently feel misunderstood. street youth are even more mistrustful of adults and public organizations, making their contact with health care professionals minimal. this combined with their risky behaviours and dangerous environment creates a population at risk for numerous health issues but with no place to have them investi· gated. at our non-government, not for profit health service designed specifically to provide a broad range of health care to street youth, professional services are provided almost entirely by volunteers. methods: using a retrospective analysis of the years of data gathered from this organization and reviewing the initial reasons gathered from youth about their needs, the success of the health centre was examined. results: all the things youth had listed as being important in a health centre have been implemented, and even more things have been added to improve the breadth and quality of services offered. the use of the health centre has increased by more than six times since its opening in . in addition, tens of thousands of visits have been paid to the health centre, costing the government and taxpayers nothing. as far as we know there is nothing else in canada that offers so many diverse and innovative services to youth in need. conclusion: it is clear from this case, that health care targeted at the needs of specific disadvan· taged populations can successfully provide them with appropriate health care. a model of accessible health care for marginalized populations can easily be developed for high impact and low cost from this successful case. toronto is one of the most ethno-racially diverse cities in the world of the estimated , , toronto residents, % ( , ) live in scarborough population growth in scarborough is faster than toronto. scarborough's population increased by % from to while toronto increased only by %. toronto's population is projected to increase by % ( ) in while scarbor· ough's will increase by %. (census canada ) low income, pove;ty, seniors, hidden homeless, new~omers to canada, the uninsured, are just a few of the issues concerning health care in our community. health care needs in scarborough are greatly impacted by diversity of ethnic and racial groups, poverty and settlement issues. this paper will share how the scarborough hospital (tsh) an urb~n communir_y hospital cares f~~ it~ community. tsh recognizes: •the changing community• b_arriers t~ accessing care • lnequalmes m health care the hospital in caring for its community pro· v ~es services that '!'e~e cu~turally, racially, and linguistically sensitive to our community. the paper will share the hospitals unique program on access and equity. the paper will share the needs in scar· borough and tsh's response to these needs: working in partnership with the local health committee, i:ne scarborough homeless co.mminee, the scarborough network of immigrant services organiza· nons a~d others. :' e paper will also share the many initiatives this urban community hospital has taken viz. community and home programs in service areas such as mental health, haemodialysis day care, t~~ home oxyg~n program, the palliative at-home program, and above all support for the volunteer clinic for the uninsured. j"'" tllu:lion: in canada's universal health care system it is generally assumed that everyone has equal access to health care. however, some immigrant groups in canada have historically been uninswed. these groups include failed refugee claimants, those overstaying their visas, and new immigrants in transition who are waiting to become eligible for health insurance. some estimates have suggested that at the present time there may be as many as one hundred thousand undocumented and thus uninsured immigrants in toronto alone. understandably, information on the characteristics of this marginalized population is very limited, since undocumented immigrants tend to have little contact with formal institutions. knowledge of the demographic characteristics of this population may aid in the development of health and social programs to better identify and meet the needs of undocumented immigrants in toronto. we conducted a review of all undocumented, uninsured patients, years of age or older at access alliance multicultural community health centre (aamchc) between and . demographic information such as age, gender, preferred language, length of time living in canada, selfreported education level and household income were recorded. rmdts: % of all adult patients at access alliance were undocumented and uninsured. % were under years of age (with a median age of years), % were women and only % spoke english. this group lived in canada for an average period of . years before they were first seen at aamchc. % of undocumented clients reported having completed at least a secondary or post-secondary education. % had self-reported household incomes of less than , $/year, while % of households reported earning less than $ , /year. the mean income per person in an average household was $/month. conchuions: uninsured individuals at aamchc were predominantly young females with limited knowledge of the english language. despite having attained a high level of education most were living well below the poverty line. recognition of these characteristics may assist in the development of health and social programs that are better adapted to meet the needs of undocumented immigrants. p - (c) sharing expertise: a role for the hospital lactation consultant in the community. badrgrmuul: st. michael's hospital is a tertiary care hospital that serves a large inner city population in downtown toronto. in order to provide care to this population, the hospital has developed a number of unique outreach roles. one such role was developed to work with pregnant and breastfeeding women living in regent park, a social housing complex located near the hospital. the population of regent park includes new immigrants, refugees and the socially disadvantaged. approach: the outreach lactation consultant provides care, as part of the canada prenatal nutrition program, in the community prenatally, in the hospital during their inpatient stay and postnatally when they return to the community. the continuity of care enhances the probability of long term successful breastfeeding. aside from the health benefits of breastmilk, breastfeeding is especially important for women who are financially needy and must depend on food banks for formula. . . lason learned: aher two years of partnership, the relationship between the an-hospital ~stpar tum experience for breastfeeding mothers and the community postpartum support, the breastfeeding rate ~thin this community is high. the professional support and visibility of the : ctation consultant, both m the hospital and in the community, contributes to the support of breastfee~m~.. . in light of ongoing funding constraints, this ha son between hospital and community could be at risk and discontinued. in light of the benefits to the mother/baby dyad, the lactation consultant as a community partner in the canada prenatal nutrition program should be safeguarded. . lldpodiu:tion: although the importance of adequate health care in pregna~cy is well recognised, ethnic disparities in utilization of prenatal care still exist in many western coun~~es. a fun~amental factor in these disparities may be language proficiency, as it influences women's ab hty. to ob~m and understand health information, to find the way in the health care system and to communicate with health care v poster sessions providers. we investigated the role of language proficiency in use and knowledge of folic acid as aspect of prenatal care in an urban multi-ethnic pregnancy c?hort. . . design: prospective cohort study. setting and parnc pants: amsterdam ~regnant women attending obstetric care providers for their first antenatal visit (n= ). country of birth defined ethnicity: the netherlands, surinam, antilles, turkey, morocco, ghana, other non-~est~m (nw) and other western (w) country. main outcome measures: knowledge about and use of.fohc a~d (fa) supplements in pregnancy, and determinants of these in diffe~~t ethnic ~~ups. deterrrunants mcl~ded age, ed~ tion, parity, pregnancy intention and dutch prof c ency. stansncs: ~ to co~p~re e~c groups, stranfied logistic regression (forward stepwise method) to explore determmants "'.'thm ethmc groups .. use of fa supplements was significantly lower among ghanaian, moroccan, turkish and other nw women ( %to %) than among dutch ( %) or other w women ( %). use amongsurinames and antillean women was intermediate ( %and %). ethnic differences in fa knowledge were similar. knowledge was the strongest determinant of use in all ethnic groups, with odds ratios (ors) ranging from . to . . language proficiency was the strongest determi~a~t of kno~ledge in ethnic groups with a mother tongue different from dutch (ors good vs. low proficiency ranging from . ro . ). educational level had a modifying role, as shown by an interaction effect between education and language proficiency in the nw group. here, the odds of having fa knowledge given a high education and good dutch proficiency was times the odds given a good proficiency but low education. conclusions: appropriate periconceptional use of folic acid supplements in non-western ethnic groups is low, reflecting an absence of knowledge that is largely determined by the inability to speak and understand the language of the habitual country. tailored interventions using communication channels most likely to address (pregnant) women from ethnic minority groups are necessary. apan from specific interventions, our results are in support of strong incentives on language education despite current political debate. introduction: recent research suggests living in an economically disadvantaged neighborhood is asso· ciated with decreased likelihood of undergoing mammography and increased risk of late-stage breast can· cer diagnosis. long distances and travel times to facilities offering low-or no-cost mammography may be imponant barriers to adherence to mammography screening recommendations for residents of economically disadvantaged neighborhoods. the purpose of this study was to examine whether facilities providing low-and no-cost screening mammography were less spatially accessible in low-income neighborhoods in chicago, and the extent to which the relationship between neighborhood income and the spatial accessibility of facilities varied by the proponion of african-american residents in the neighborhood. methods: the sample consisted of chicago neighborhoods. for each neighborhood, we con· structed three measures of the spatial accessibility of facilities: street network distance to the nearest facility, public transportation travel time to the nearest facility, and shortest automobile travel time to a facility. using decennial census data, we characterized the neighborhoods according to proportion of residents with incomes below the poverty line, proportion of residents in each of four raciavethnic groups (african-american, latino, white, and other), and population density. we used ordinary least squares (ols) and spatial exogenous lag regression to examine relationships. model estimated the relationship between neighborhood poverty and the spatial accessibility of facilities, adjusting for raciaveth· nic composition and population density. model added a multiplicative interaction term between neighborhood poverty and african-american. restllts: we identified deven facilities that provided low-or no-cost screening mammography to chicago residents in . we found that the distance and travel times via automobile and public trans· portation to facilities generally decreased as neighborhood poveny increased. however, we also found that the ~egative associations between neighborhood poverty and two of the spatial accessibility mea· sures -distance and public transportation travel time -were less strong in neighborhoods with the highest proponions of african-american residents. among neighborhoods in the highest tertile for poveny, th~ mean distance and mean public transportation travel time to facilities were over twice as long in neighborhoods in the highest tertile than in those in the lowest tenile of african-american residents. . ~ persistent socioeconomic and racial/ethnic disparities in breast cancer stage at diagno-s ~nd su~ val suggest that ensuring an equitable distribution of affordable mammography is a worth-w~e policy .goal. the ~~dy sugges~ that ~ture investigations should consider both neighborhood soc oecono d c charactensbes and rac avethmc composition when examining the spatial distribution of health resources. , ) . epidemiological data suggest tha~ hiv prevalence among msm is over % in some metropolitan cities, such .as beijing (ibid.). due to widespread homophobia in chinese society, however, this population remains invisible within current health/social services. lack of research on sexuality, specifically homosexuality, has impaired our understanding of health and health practices of chinese msm. focusing on the illness experiences of chinese msm with hiv/aids, this paper explores the socio-cultural impacts of hiv/ aids on this group. the data used for this paper were collected through semi-constructed in-depth face-toiace interviews with adult plwhas (including msm) in beijing, china. with the permission of the participants, the interviews were audio-taped or recorded in notes. the transcribed interviews and interview notes were analyzed by using n-vivo, a software program for qualitative data analysis. this phenomenological study aimed to understand the experiences chinese plwhas (including msm) from their own perspectives. results: it is found that the illness experiences of chinese msm with hiv/aids are profoundly shaped by the socio-cultural meanings of homosexuality, which are further complicated by the dominant discourses on hiv/aids in china. at a macro level, homophobia in the larger society has decreased the capability of this group to respond to this epidemic in a more efficient way. at a meso level, aids-phobia within the chinese msm circuits has prevented this group from openly confronting this disease and offering support to those who are already affected by it. at a micro level, however, these hiv-infected/ affected msm have tried their best to locate spaces to live and to construct hope for their future lives despite various barriers within family, community, and the larger society. this study suggests that facilitating chinese msm's response to the aids crisis urgently requires bridging awareness, commitment, knowledge and resources both within and without this group. it also illustrates the importance of understanding homosexuality in the local context of hiv i aids, which will be helpful for developing culturally sensitive hiv/aids programs for this population on the community, national and international levels. introduction: having a regular family doctor (rfd) is known to be positively correlated with a good medical follow up, including access to preventive and/or chronic care. inversely, a lack of primary care may lead to high rates of avoidable hospitalizations, especially among poor people and/or in underserved neighbourhoods. in such a matter, a recent comparative study showed that paris was better ranged than other cities, such as nyc, tokyo or london. nevertheless, despite a quasi universal health insurance and a high density of general practitioners, a noticeable fraction of the paris population does not have any regular physician and we aimed to understand who they are and for what reasons rhey don't have any rfd. mdbods: cross sectional population survey among a random sample of households in ~nderpriv ileged neighbourhoods in paris inner city, performed in , using a face-to-face quest nna re collecr- ng more than social and health characteristics. ruults: a quarter ( . %) of rhe study popularion did not have any rfd. this proporrion was iignificantly higher among male (or= . , %ci = [ . - . ), younger (e.g. or - /> .s l _= ._oo, " .ci = ( . - . )), and/or unemployed (or = . , %ci = ij . - . _ people. in multtvanate analysis, after a full adjustment on gender, age, health status, health insura~ce, income, occupat n and tducation level, we observed significant associations between having no rfd and: ~arrtal and_ pare~t hood status (e.g. or single no kids/in couple+kids = . , %ci = ( . - . ()~ quality of relattonsh ps with neighbours (or bad/good= . , %ci = [ . - . )), and length of residence m the neighbourhood (with a dose/effect statistical relationship). . co clusion: gender, age, employment status, mariral and parenthood stat~s as well as ~e gh bourhood anchorage seem to be major predictors of having a rfd, even when um.versa! health i~sur ance has reduced most of financial barriers. in urban contexts, where residential migrattons and single lift (or family ruptures) are frequent, specific information may be conducted to encourage people to ket rfd. :tu~y tries to assess the health effects and costs and also analyse the availability and accessibility to health care for poor. . methods: data for this study was collected by a survey on households of the local community living near the factories and households where radiation hazard w~s n?~ present. ~~art from mor· bidity status and health expenditure, data was collected ~n access, a~ail~b .hty and eff c ency of healrh care. a discriminant analysis was done to identify the vanables that d scnmmate between the study and control group households in terms of health care pattern. a contingent valuation survey was also undertaken among the study group to find out the factors affecting their willingness to pay for health insurance and was analysed using logit model. results: the health costs and indebtedness in families of the study group was high as compared to control group households and this was mainly due to high health expenditure. the discriminant analysis showed that expenditure incurred by private hospital inpatient and outpatient expenditure were significant variables, which discriminated between the two types of households. the logit analysis showed !hat variables like indebtedness of households, better health care and presence of radiation induced illnesses were significant factors influencing willingness to pay for health insurance. the study showed that study group households were dependent on private sector to get better health care and there were problems with access and availability at the public sector. conclusion: the study found out that the quality of life of the local community is poor due to health effects of radiation and the burden of radiation induced illnesses are so high for them. there is an urgent need for government intervention in this matter. there is also a need for the public sector to be efficient to cater to the needs of the poor. a health insurance or other forms of support to these households will improve the quality for health care services, better and fast access to health care facilities and reduces the financial burden of the local fishing community. the prevalence of substance abuse is an increasing problem among low-income urban women in puerto rico. latina access to treatment may play an important role in remission from substance abuse. little is known, however, about latinas' access to drug treatment. further, the role of social capital in substance abuse treatment utilization is unknown. this study examines the relative roles of social capital and other factors in obtaining substance abuse treatment, in a three-wave longitudinal study of women ages - living in high-risk urban areas of puerto rico, the inner city latina drug using study (icldus). social capital is measured at the individual level and includes variables from social support and networks, familism, physical environment, and religion instruments of the icdus. the study also elucidates the role of treatment received during the study in bringing about changes in social capital. the theoretical framework used in exploring the utilization of substance abuse treatment is the social support approach to social capital. the research addresses three main questions: ( t) does social capital predict parti~ipating in treatment programs? ( ) does participation in drug treatment programs increase social capital?, and ( ) is there a significant difference among treatment modalities in affecting change in ~ial capital? the findings revealed no significant association between levels of social capital and gettmg treatment. also, women who received drug treatment did not increase their levels of social capital. the findings, however, revealed a number of significant predictors of social capital and receiving drug ~buse treatment. predictors of social capital at wave iii include employment status, total monthly mcoi:rie, and baseline social capital. predictors of receiving drug abuse treatment include perception of physical health and total amount of money spent on drugs. other different variables were associated to treatment receipt prior to the icldus study. no significant difference in changes of social capital was found among users of different treatment modalities. this research represents an initial attempt to elucidate the two-way relationship between social capital and substance abuse treatment. more work is necessary to unden~nd. ~e role of political forces that promote social inequalities in creating drug abuse problems and ava lab hty of treatment; the relationship between the benefits provided by current treatment poster sessions v sctrings and treatment-seeking behaviors; the paths of recovery; and the efficacy and effectiveness of the trtaanent. and alejandro jadad health professionals in urban centres must meet the challenge of providing equitable care to a population with diverse needs and abilities to access and use available services. within the canadian health care system, providers are time-pressured and ill-equipped to deal with patients who face barriers of poverty, literacy, language, culture and social isolation. directing patients to needed supportive care services is even more difficult than providing them with appropriate technical care. a large proportion of the population do not have equitable access to services and face major problems navigating complex systems. new approaches are needed to bridge across diverse populations and reach out to underserved patients most in need. the objective of this project was to develop an innovative program to help underserved cancer patients access, understand and use needed health and social services. it implemented and evaluated, a pilot intervention employing trained 'personal health coaches' to assist underserved patients from a variety of ethno-linguistic, socio economic and educational backgrounds to meet their supportive cancer care needs. the intervention was tested with a group of underserved cancer patients at the princess margaret hospital, toronto. personal coaches helped patients identify needs, access information, and use supportive care services. triangulation was used to compare and contrast multiple sources of quantitative and qualitative evaluation data provided by patients, personal health coaches, and health care providers to assess needs, barriers and the effectiveness of the coach program. many patients faced multiple barriers and had complex unmet needs. barriers of poverty and language were the easiest to detect. a formal, systematic method to identify and meet supportive care needs was not in place at the hospital. however, when patients were referred to the program, an overwhelming majority of participants were highly satisfied with the intervention. the service also appeared to have important implications for improved technical health care by ensuring attendance at appointments, arranging transportation and translation services, encouraging adherence to therapy and mitigating financial hardship -using existing community services. this intervention identified a new approach that was effective in helping very needy patients navigate health and social services systems. such programs hold potential to improve both emotional and physical health out· comes. since assistance from a coach at the right time can prevent crises, it can create efficiencies in the health system. the successful use of individuals who were not licensed health professionals for this purpose has implications for health manpower planning. needle exchange programs (neps) have been distributing harm reduction materials in toronto since . counterfit harm reduction program is a small project operated out of a community health centre in south-east toronto. the project is operated by a single full-time coordinator, one pan-rime mobile outreach worker and two peers who work a few hours each week. all of counterfit's staff, peers, and volunteers identify themselves as active illicit drug users. yet the program dis~rib utes more needles and safer crack using kits and serves more illicit drug u~rs t~an the comb ~e~ number of all neps in toronto. this presentation will discuss the reasons behind this success, .s~ f cally the extended hours of operation, delivery models, and the inclusion of an. extremely marg ~ahzed community in all aspects of program design, implementation and eva.luat ?n. ~ounterfit was recently evaluated by drs. peggy milson and carol strike, two leading ep dem olog st and researchers in the hiv and nep fields in toronto and below are some of their findings: "the program has experienced considerable success in delivering a high quality, accessible and well-used program .... the pro· gram has allowed (service users) to become active participants in providing. services to others and has resulted in true community development in the best sense. " ... counterf t has ~~n verr succe~sful attracting and retaining clients, developing an effective peer-based model an.d assisting chen~s ~ th a vast range of issues .... the program has become a model for harm red~ctmn progr~ms withm the province of ontario and beyond." in june , the association of ?ntano co~mumty heal~~ <:en· ires recognized counterfit's acheivements with the excellence m community health initiatives award. in kenya, health outcomes and the performance of government health service~ have det~riorated since the late s, trends which coincide with a period of severe resource constramts necessitated by macro-economic stabilization measures after the extreme neo-liberalism of the s. when the govern· ment withdrew from direct service provision as reform trends and donor advocacy suggested, how does it perform its new indirect role of managing relations with new direct health services providers in terms of regulating, enabling, and managing relations with these health services providers? in this paper therefore, we seek to investigate how healthcare access and availability in the slums of nairobi has been impacted upon by the government's withdrawal from direct health care provision. the methodology involved col· leering primary data by conducting field visits to health institutions located in the slum areas of kibera and korogocho in nairobi. purposive random sampling was utilized in this study because this sampling technique allowed the researcher(s) to select those health care seekers and providers who had the required information with respect to the objectives of the study. in-depth interviews using a semi-structured ques· tionnaire were administered ro key informants in health care institutions. this sought to explore ways in which the government and the private sector had responded and addressed in practical terms to new demands of health care provision following the structural adjustment programmes of the s. this was complemented by secondary literature review of publications and records of key governmental, bilateral and multilateral development partners in nairobi. the study notes a number of weaknesses especially of kenya's ministry of health to perform its expected roles such as managing user fee revenue and financial sustainability of health insurance systems. this changing face of health services provision in kenya there· fore creates a complex situation, which demands greater understanding of the roles of competition and choice, regulatory structures and models of financing in shaving the evolution of health services. we rec· ommend that the introduction of user fees, decentralization of service provision and contracting-out of non-clinical to private and voluntary agencies require a new management culture, and new and clear insri· tutional relationships. experience with private sector involvement in health projects underlines the need not only for innovative financial structures to deal with a multitude of contractual, political, market and risks, but also building credible structures to ensure that health services projects are environmentally responsive, socially sensitive, economically viable, and politically feasible. purpose: the purpose of this study is to examine the status of mammography screening utilization and its predictors among muslim women living in southern california. methods: we conducted a cross-sectional study that included women aged ::!: years. we col· leered data using a questionnaire in the primary language of the subjects. the questionnaire included questions on demography; practices of breast self-examination (bse) and clinical breast examination (cbe); utilization of mammography; and family history of breast cancer. bivariate and multiple logistic regression analyses were performed to estimate the odds ratios of mammography use as a function of demographic and other predictor variables. . results: among the women, % were married, % were - years old, and % had family h story of breast cancer. thirty-two percent of the participating women never practiced bse and % had not undergone cbe during the past two years. the data indicated that % of the women did not have mammography in the last two years. logistic regression analysis showed that age ( r= . , % confi· dcnc~ interval (cl)=l. - . ), having clinical breast examination ( r= . , % cl= . - . ), and practtce of self-breast examination ( r= . , % cl= . - . ), were strong predictors of mammography use . . conclusions: the data point to the need for intervention targeting muslim women to inform and motivate th.cm a~ut practices for early detection of breast cancer and screening. further studies are needed to investigate the factors associated with low utilization of mammography among muslim women population in california. we conducted a review of the scientific literature and° government documents to describe ditnational health care program "barrio adentro" (inside the neighborhood). we also conducted qualiurivt interviews with members of the local health committees in urban settings to descrihe the comm unity participation component of the program. rtsmlts: until recently, the venezuelan public health system was characterized by a lack or limited access w health care ( % of the population) and long waiting lists that amounted to denial of service. moit than half of the mds worked in the five wealthiest metropolitan areas of the country. jn the spring oi , a pilot program hired cuban mds to live in the slums of caracas to provide health care to piople who had previously been marginalized from social programs. the program underwent a massive expansion and in only two years , cuban and , venezuelan health care providers were working acmss the country. they provide a daily average of - medical consultations and home visits, c lly out neighborhood rounds, and deliver health prevention initiatives, including immunization programs. they also provide generic medicines at no cost to patients, which treat % of presenting ill-ij!m, barrio adentro aims to build , clinics (primary care), , diagnostic and rehabilitation ctnrres (secondary care), and upgrade the current hospital infrastructure (tertiary care). local health committees survey the community to identify needs and organize a variety of lobby groups to improve dit material conditions of the community. last year, barrio adentro conducted . times the medical visits conducted by the ministry of health. the philosophy of care follows an integrated approach where btalrh is related to housing, education, employment, sports, environment, and food security. conclusions: barrio adentro is a unique collaboration between low-middle income countries to provide health care to people who have been traditionally excluded from social programs. this program shows that it is possible to develop an effective international collaboration based on participatory democracy. low-income americans are at the greatest risk of being uninsured and often face multiple health concerns. this evaluation of the neighborhood health initiative (nh!), an organization which uses multiple programmatic approaches to meet the multiple health needs of clients, reflected the program's many activities and the clients' many service needs. nh! serves low-income, underserved, and hard-to-reach residents in the des moines enterprise community. multiple approaches (fourth-generation evaluation, grounded theory, strengths-and needs-based) and methods (staff and client interviews, concept mapping, observations, qualitative and quantitative analysis) were used to achieve that reflection. results indicate good targeting of residents in the zip code and positive findings in the way of health insurance coverage and reported unmet health needs of clients. program activities were found to match client nttds, validating the organization\'s assessment of clients. important components of nhi were the staff composition and that the organization had become part of both the formal and informal networks. nhi positioned as a link between the target population and local health and social sc:rvice agencies, working to connect residents with services and information as well as aid local agencies in reaching this underserved population. p - (c) welfare: definition by new york city maribeth gregory for an individual who resides in new york city, to obtain health insurance under the medicaid policy one must fall under certain criteria .. (new york city's welfare programs ) if the individual _is on ssi or earns equal to or less than $ per month, he is entitled to receive no more than $ , m resources. a family the size of two would need to earn less than $ per month to qualify for no greater than ss, worth of medicaid benefits. a family of three would qualify for $ , is they earned less than $ per month and so on. introduction: the vancouver gay communiry has a significant number of asian descendan!l. because of their double minority status of being gay and asian, many asian men who have sex with men (msm) are struggling with unique issues. dealing with racism in both mainstream society and the gay communiry, cultural differences, traditional family relations, and language challenges can be some of their everyday srruggles. however, culturally, sexually, and linguistically specific services for asian msm are very limited. a lack of availability and accessibiliry of culturally appropriate sexual health services isolates asian msm from mainstream society, the gay community, and their own cultural communities, deprives them of self-esteem, and endangers their sexual well-being. this research focuses on the qualita· tive narrative voices of asian msm who express their issues related to their sexualiry and the challenges of asking for help. by listening to their voices, practitioners can get ideas of what we are missing and how we need to intervene in order to reach asian msm and ensure their sexual health. methods: since many asian msm are very discreet, it is crucial to build up trust relationships between the researcher and asian msm in order to collect qualitative data. for this reason, a community based participatory research model was adopted by forming a six week discussion group for asian msm. in each group session, the researcher tape recorded the discussion, observed interactions among the participants, and analyzed the data by focusing on participants' personal thoughts, experiences, and emotions for given discussion topics. ra lts: many asian msm share challenges such as coping with a language barrier, cultural differ· ences for interpreting issues and problems, and westerncentrism when they approach existing sexual health services. moreover, because of their fear of being disclosed in their small ethnic communities, a lot of asian msm feel insecure about seeking sexual health services when their issues are related to their sexual orientation. conclflsion: sexual health services should contain multilingual and multicultural capacities to meet minority clients' needs. for asian msm, outreach may be a more effective way to provide them with accessible sexual health services since many asian msm are closeted and are therefore reluctant to approach the services. building a communiry for asian msm is also a significant step toward including them in healthcare services. a communiry-based panicipatory approach can help to build a community for asian msm since it creates a rrust relationship between a worker and clients. p - (c) identifying key techniques to sustain interpretation services for assisting newcomers isolated by linguistic and cultural barriers from accessing health services s. gopi krishna lntrodaetion: the greater toronto area (gta) is home to many newcomer immigrants and other vulnerable groups who can't access health resources due to linguistic, cultural and systemic barriers. linguistic and cultural issues are of special concern to suburbs like scarborough, which is home to thousands of newcomer immigrants and refugees lacking fluency in english. multilingual community ~nterpreter. service~ (mcis) is a non-profit social service organization mandated to provide high quality mterpretanon services. to help newcomers access health services, mcis partnered with the scarborough network of immigrant serving organizations (sniso) to recruit and train volunteer interpreters to accompany clienrs lacking fluency in english and interpret for them to access health services at various locati?ns, incl~~ing communiry ~c:-lth centres/social service agencies and hospitals. the model envisioned agencies recruin~ and mcis ~.mm.g and creating an online database of pooled interpreter resources. this da.tabase, acces& bl~ to all pama~~g ?rganization is to be maintained through administrative/member · ship fees to. be ~ d by each parnapanng organization. this paper analyzes the results of the project, defines and identifies suc:cases before providing a detailed analysis for the reasons for the success . . methods:. this ~per~ q~ntitative (i.e. client numben) and qualitative analysis (i.e. results of key •~ormant m~rv ews with semce ~sers and interpreters) to analyze the project development, training and mplementanon phases of the project. it then identifies the successes and failures through the afore· mentioned analysis. poster sessions vss resljts: the results of the analysis can be summarized as: • the program saw modest success both ia l?lllls of numbers of clients served as well as sustainability at various locations, except in the hospital iririog. o the success of the program rests strongly on the commitment of not just the volunteer interprmr, but on service users acknowledgments through providing transponation allowance, small honororia, letter of reference etc. • the hospital sustained the program better at the hospital due to the iolume and nature of the need, as well as innate capacity for managing and acknowledging volunceers. collc/llsion: it is possible to facilitate and sustain vulnerable newcomer immigrants access to health !ul'ices through the training and commitment of an interpreter volunteer core. acknowledging volunteer commitment is key to the sustenance of the project. this finding is important to immigration and health policy given the significant numbers of newcomer immigrants arriving in canada's urban communities. nity program was established in to provide support to people dying at home, especially those who were waiting for admission to the resi<lential hospice. with the advent of haart and corresponding challenges for people living with hiv/aids in the community, the community program has developed a unique case management approach. this model features an interdisciplinary team providing a clientdrivcn service. the case manager provides continuity of care to clients in a variety of settings both within and outside of the health care system. a case study is used to demonstrate how formal and informal networks of support facilitate efficient and appropriate resource utilization to promote client health. this case study demonstrates the value of consistent coordination with a client who has complex physical, spiritual, substance use and mental health needs. the authors will show how they liaised with the housing authority, police, social services as well as the family physician, clinic staff and a hospital emergtncy room to ensure this client did not fall between the cracks. tarek hussain recognition of the importance of community involvement and sectoral cooperation in health and !ocial services, formalized in alma-ata declaration in , was reinforced at riga meeting held at the mid·point between alma-ata and the year . then at the th anniversary of alma-ata declaration, ir was declared that 'primary health care is everybody's business'. health does not exist in isolation. health cannot be defined only as an outcome of 'medical care' but also as one of 'social action'; the responsibility of disease prevention and health promotion rests not only on governments, but also with don·govemmentorgan izations, the community, and individuals. the major accomplishment to date may be that rhere is growing realization in the health sector that community involvement is more than a political right-it is absolute necessary. lessons have learned during the implementation of disease-specific l'cltical programmes, such as cdd, ari, and epi; first, integrated and holistic approaches to childcare art needed, and second, the need for community involvement has become evident. imc! is a broad inte-gra ed strategy with an overall objective contributing to reducing child morbidity and mortality in developing countries. and one of the imci components, 'community !mci', which is now broadening ~s an entry point for child-focused community development initiatives. community jmcl/c~ ld health is ~n mtcgrated approach to the promotion of key family and community practices that have impact on: child growth and development, disease prevention, home care for sick, malnourished child~en, a.nd care-seekmg behavior and compliance with advice and treatment. the presentation addres~es, m brief, the ~evel opinent of community !mci, operational aspect of community/im cl, key strategies and tools ava la~le for implementation of c/imci. the paper draws some successful programme examples on working logether for imc! with the community in various countries which had substantial benefns on programme outcomes. p - t (c) healthy child screening: an innovative service initiative ann-marie marcolin and joyce allen . introduction: with mounting attention for creative and integrated models of c~re .that are populallon and community focused, the healthy child screening initiative achiev.es t~ese pnncipl~s and more! . • parkdale high park rotary (sponsorship) the heal~h ~h ld scree? ?g is a ~opl~-centred model of care. agency and professional sector-specific silos are ehmmated, ~rov dmg f~~ hes wit~ one-sto~ access to primary prevention services in a local school gym! children at nsk are rece vmg early mtervent n and appropriate referrals to the right care provider, at the right time a~d in t~e right place. further, with a complimentary focus on prevention, the program serves to keep at nsk children healthy. healthy child screening results: the service model is developed around four distinct phases: ) planned outreach; ) coordinated intake and registration; ) interdisciplinary screening; and ) targeted referral. since the fall and through six collaborative healthy child screenings children ranging in age from to have benefited from this unique service model of care. conclusion: the presentation will provide practical information on the development and implementation of the model. there will also be a focus on lessons learned in building community service provider-hospital relationships. according to statistics canada ( ) % of the toronto population was born outside of canada and % were new immigrants. immigrants often arrive in canada in superior health compared to the canadian born population, but they lose this health advantage over time. changes in immigrant health status over time may be attributed to a variety of factors including barriers to accessing and receiving care as well as limitations in the mainstream health service organizations and their approaches to health care delivery (hyman, ) . for example, immigrant women are less likely to receive pap tests, which places them at a greater risk for developing cervical cancer. similarly, immigrant women receive less mammography screening than their canadian counterparts. the immigrant women's health centre mobile health unit (mhu) was created as an alternative care delivery model to address the need for increased accessibility as well as culturally and linguistically appropriate reproductive health care. toronto western hospital and the immigrant women's health centre have formed a collaborative partnership which incorporates a primary care nurse practitioner and lay ethnocultural counselors providing care on the mhu. currently, a qualitative ethnonursing study is underway to understand the unique experiences of women using the mhu for their reproductive health care as well as the perspectives of the mhu health care providers. based on a literature review and preliminary findings from provider and participant interviews, the proposed presentation will address the themes of health status for immigrant and refugee women, accessibility issues as well strategies to improve their reproductive health care. we will discuss benefits as well as limitations to health care provision using this alternative service delivery model. michael carden, brian edlin, andrew talal, elizabeth getter, and marla shu lntrod.ction: to date most active drug users have not had access to treatment for hepatitis c virus (hcv) infection and substantial barriers continue to exist that interfere with treatment availability for this population. methods: active illicit drug users interested in pursuing hcv care and treatment were recruited in partnership w~th co~munity-based organizations (cbo's) in new york city. baseline data were collected on quahty of hfe, substance use patterns, depression, health care utilization, hcv health beliefs and other relev.ant variables. medical evaluations were conducted, including liver biopsy when indicated, an~ treatment ts ~ffered when no contraindications are present. participants also receive psychiatric evaluahons to determme the appropriateness of interferon treatment. renlts: fifteen individuals have been recruited to date and received an initial medical evaluation. the mean age was years and _the average age of initial heroin or cocaine use was . . eight ( %) ha~ been homeless at least once m the last months and s ( %) were homeless for most or all of this penod. fourteen ( %) had a history of injection drug use with the mean age at first injection being s frsewons v ,an. elrven persc.!ns ( %) reported inje~~ng .heroin or cocaine within the last days while the .wing four ( l'o) reported regular non-m ect on use of cocaine and street-obtained benzodiazepines. sijiy seven percent of the sample (n= ) reported ever being referred to hcv treatment while ( t % ) ftponeddiattreann~nt had been offered by~ ~e.dical provider. none had ever received a liver biopsy or araanent. most believed that hcv was a s gmf cant threat to their health ( %) and that there was a pm)dchance they would eventually die if their hepatitis c was not treated ( %). though individuals % believed that there was no cure for hcv, ( %) reported that they would initiate treatment if i was recommended by their doctor. thirteen ( %) had a current psychiatric diagnosis including «pmsion, anxiety disorder, schizophrenia, schizoaffective disorder, and borderline and antisocial persooaliry disorders. among eight individuals who had the beck depression inventory administered, the mean score was . . attendance rates were % ( / ) at scheduled medical and psychiatric ppointments and % ( / ) at liver biopsy. <andtuions: active drug users, despite experiencing multiple psycho-social problems, can be mgaged in hcv care using a multidisciplinary approach, but require intensive follow-up support. hcv aunnent of active drug users should not be dismissed. n- (c) antiretroviral therapy in mv infected infants: when to initiate therapy an african experience kingsley okonkwo, ademola adeyemo, israel sokeye, and nwaife umeike /""°""ction: as technology for early diagnosis of human immunodeficiency virus [hiv] improves, m to commence highly active antiretroviral therapy [haarn is yet to be fully evaluated. this prospective study describes our initial experience with early haart in hiv infected nigerian infants and rqions the outcome. we also analyzed the socioeconomic implications of early haart therapy in infants in the african setting. method: hiv infected infants were started on haart before months and followed up at mkly intervals.we monitored baseline and monthly cd . conclusion: initial results suggest early haart before months resulted. in improv~d out~ome in african children. treatment appears to be as effective as in developed counmes. in. a~nca as. m most developing countries with limited resources it is possible and effective to use haart m ~~ants if p~oper llloniroring facilities are available. however the occurrence of long-term drug related tox c ty and mk of emergence of resistant viral strains create need for further evaluation of haart in infants. background: most risk factors for cardiovascular disease (cvd) can be mitigated through ~th clinical interventions and lifestyle change. we used data from a telephone survey of new york city (nyc) adults to characterize health care access and healthy behavior among those with three or more cvd risk factors. methods: the study population included respondents to the nyc community health survey (n= , ) self-reporting~ of the following: smoking, diabetes, high cholesterol level, high blood pres· sure, body mass index > , and age > (males) or > (females) (n= , ). results: based on self-report, an estimated . , ( %) of nyc adults have~ or more cvd risk factors. this population is % male, % white, % black, and % with s years of education. most report good access to health care, indicated by having health insurance ( %), regular doctor ( %), their blood pressure checked within last months ( %), and their choles· terol checked within the past year ( % ). only % reported getting at least minutes of exercise ~ times per week and only % eating ~ servings of fruits and vegetables the previous day. among current smokers, % attempted to quit in past months, but only % used medication or counseling. implications: these data suggest that most nyc adults known to be at high risk for cvd have access to regular health care, but most do not engage in healthy lifestyle or, if they smoke, attempt effective quit strategies. more clinic-based and population-level interventions are needed to support lifestyle change among those at high risk of cvd. introduction: recently, much interest has been directed at "obesogenic" (obesity-promoting) (swinburn, egger & raza, ) built environments, and at geographic information systems (gis) as a tool for their exploration. a major geographical concept is accessibility, or the ease of moving from an origin to a destination point, which has been recently explored in several health promotion-related stud· ies. there are several methods of calculating accessibility to an urban feature, each with its own strengths, drawbacks and level of precision that can be applied to various health promotion research issues. the purpose of this paper is to describe, compare and contrast four common methods of calculating accessibility to urban amenities in terms of their utility to obesity-related health promotion research. practical and conceptual issues surrounding these methods are introduced and discussed with the intent of providing health promotion researchers with information useful for selecting the most appropria e accessibility method for their research goal~ ~ethod: this paper describes methodological insights from two studies, both of which assessed the neighbourhood-level accessibility of fast-food establishments in edmonton, canada -one which used a relatively simple coverage method and one which used a more complex minimum cos method. res.its: both methods of calculating accessibility revealed similar patterns of high and low access to fast-food outlets. however, a major drawback of both methods is that they assume the characteristics of the a~e~ities and of the populations using them are all the same, and are static. the gravity potential method is introduced as an alternative, since it is ·capable of factoring in measures of quality and choice. a n~mber of conceptual and pr~ctical iss~es, illustrated by the example of situational influences on food choice, make the use of the gravity potential model unwieldy for health promotion research into sociallydetermined conditions such as obesity. co.nclusions: i~ ~ommended that geographical approaches be used in partnership with, or as a foun~ation for, ~admonal exploratory methodologies such as group interviews or other forms of commumty consultation that are more inclusive and representative of the populations of interest. qilhl in los angeles county ,,..ia shaheen, richard casey, fernando cardenas, holman arthurs, and richard baker ~the retinomax autorefractor has been used for vision screening of preschool age childien. ir bas been suggested to be used and test school age children but not been validated in this age poup. ob;taiw: to compare the results of retinomax autorefractor with findings from a comprehensive i!' examination using wet retinoscopy for refractive error. mllhods: children - years old recruited from elementary schools at los angeles county were iaml with snellen's chart and the retinomax autorefractor and bad comprehensive eye examination with dilation. the proportion of children with abnormal eye examination as well as diesensitiviry and specificity of the screening tools using retinomax autorefractor alone and in combinalion wirh snellen's chart. results of the children enrolled in the study (average age= . ± . years; age range, - years), ?% had abnormal eye examination using retinoscopy with dilation. for the lerinomax, the sensitivity was % ( % confidence interval [ci] %- %), and the specificity was % ( % ci, %- o/o). simultaneous testing using snellen's chart and retinomax resulted in gain in sitiviry ( %, % cl= , ), and loss in specificity ( %, % cl= %- %). the study showed that screening school age children with retinomax autorefractor could identify most cases with abnormal vision but would be associated with many false-positive results. simuhaneous resting using snellen's chart and retinomax maximize the case finding but with very low specificiry. mdhotjs: a language-stratified, random sample of members of the college of family physicians of canada received a confidential survey. the questionnaire collected data on socio-demographic characteristics, medical training, practice type, setting and hcv-related care practices. the self-adminisratd questionnaire was also made available to participants for completion on the internet. batdti: response proportion was %. median age was years ( % female) and the proporlionoffrench questionnaires was %. approximately % had completed family medicine residency lllining in canada; median year of training completion was . sixty-seven percent, % and % work in private offices/clinics, community hospitals and emergency departments, respectively. regarding ~practices, % had ever requested a hcv test and % of physicians had screened for hcv iafrction in rhe past months· median number of tests was . while % reported having no hcv-uaed patients in their practic~, % had - hcv-infected patients. regarding the level of hcv care provided, . % provide ongoing advanced hcv care including treatment and dose monitoring for ctmduions: in this sample of canadian family physicians, most had pro~ided hcv screening. to •least one patient in the past year. less than half had - hcv-infected patients and % provide ~:relared care the role of socio-demographic factors, medical training as wel_i as hcv ca~e percep-lldas rhe provision of appropriate hcv screening will be examined and described at the time of the canference. ' - (c) healthcare services: the context of nepal meen poudyal chhetri """ tl.ction healthcare service is related with the human rights and fundamental righ~ of the ci~ ciaaiuntry. however, the growing demand foi health care services, quality heal~care service, accessib b~ id die mass population and paucity of funds are the different but interrelated issues to .be ~ddressed. m nepat. n view of this context, public health sector in nepal is among other sectors, which is struggling -.i for scarce resources. . . . nepal, the problems in the field of healthcare servic~s do not bnut ~o the. paucity of faads and resources only, but there are other problems like: rural -urban imbalance, regional unbalance, poster sessio~ f the ll ·m ·ted resources poor healthcare services, inequity and inaccessibility of the poor management o , . poor people of the rural, remote and hilly areas for the healthcare services and so on.. . . . · . i f ct the best resource allocation is the one that max m zes t e sum o m ivi ua s u · ea t services. n a , · h d' ·b · · · h . ·t effi.ciency and efficient management are correlated. it might be t e re istn utmn of mes. ence, equi y, . . . . . income or redistribution of services. moreover, maximizanon of available resources, qua tty healthcare services and efficient management of them are the very important and necessary tools and techmques to meet the growing demand and quality healthcare services in nepal. p - (a) an jn-depth analysis of medical detox clients to assist in evidence based decision making xin li, huiying sun, ajay puri, david marsh, and aslam anis introduction: problematic substance use represents an ever-increasing public health challenge. in the vancouver coastal health (vch) region, there are more than , individuals having some probability of drug or alcohol dependence. to accommodate this potential demand for addiction related services, vch provides various services and treatment, including four levels of withdrawal management services (wms). clients seeking wms are screened and referred to appropriate services through a central telephone intake service (access i). the present study seeks to rigorously evaluate one of the services, vancouver detox, a medically monitored -bed residential detox facility, and its clients. doing so will allow decision makers to utilize evidence based decision-making in order to improve the accessibility and efficiency of wms, and therefore, the health of these clients. methods: we extract one-year data (october , -september , from an efficient and comprehensive database. the occupancy rate of the detox centre along with the clients' wait time for service and length of stay (los) are calculated. in addition, the effect of seasonality on these variables and the impact of the once per month welfare check issuance on the occupancy rate are also evaluated. results: among the clients (median age , % male) who were referred by access! to vancouver detox over the one-year period, were admitted. the majority ( %) of those who are not admitted are either lost to follow up (i.e., clients not having a fixed address or telephone) or declined service at time of callback. the median wait time was day [q -ql: - ], the median los was days iq -qt: - ], and the average bed occupancy rate was %. however, during the threeday welfare check issue period the occupancy rate was lower compared to the other days of the year % vs. %, p conclusion: our analysis indicates that there was a relatively short wait time at vancouver detox, however % of the potential clients were not served. in addition, the occupancy rate declined during the welfare check issuance period and during the summer. this suggests that accessibility and efficiency at vancouver detox could be improved by specifically addressing these factors. background: intimate partner violence (ipv) is associated with acute and chronic physical and men· tal health outcomes for women resulting in greater use of health services. yet, a vast literature attests to cultural variations in perceptions of health and help-seeking behaviour. fewer studies have examined differences in perceptions of ipv among women from ethnocultural communities. the recognition, definition, and understanding of ipv, as well as the language used to describe these experiences, may be different in these communities. as such, a woman's response, including whether or not to disclose or seek help, may vary according to her understanding of the problem. methods: this pilot study explores the influence of cultural factors on perceptions of and responses to ipv among canadian born and immigrant young women. in-depth focus group interviews were con· ducted with women, aged to years, living in toronto. open-ended and semi-structured interview questions were designed to elicit information regarding how young women socially construct jpv and where they would go to receive help. interviews were transcribed, then read and independently coded by the research team. codes were compared and disagreements resolved. qualitative software qsr n was used to assist with data management. . ruu~ts_: res~nses_abo~t what constitutes ipv were similar across the study groups. when considering specific ab.us ve ~ tuanons and types of relationships, participants held fairly relativistic views about ipv, especially with regard to help-seeking behaviour. cultural differences in beliefs about normaive m;ile/femal~ relations. familial.roles, and customs governing acceptable behaviours influenced partictpants perceptions about what n ght be helpful to abused women. interview data highlight the social l ter srnfons v suucrural _impact these factors ha:e on you?g women and provide details regarding the dynamics of cibnocultur~ m~uences on help-~eekmg behav ur: t~e ro~e of such factors such as gender inequality within rtlaoo?sh ps and t_he ~erce ved degree of ~oc al solat on and support nerworks are highlighted. collc~ the~ findmgs unde~score the _ mporta_nc_e of understanding cultural variations in percrprions of ipv ~ relanon to ~elp-seekmg beha~ ':'ur. th s_mformation is critical for health professionals iodiey may connnue developmg culturally sensmve practices, including screening guidelines and protorol s. ln addition, _this study demonstr~tes that focus group interviews are valuable for engaging young romen in discussions about ipv, helpmg them to 'name' their experiences, and consider sources of help when warranted. p -s (a) health problems and health care use of young drug users in amsterdam .wieke krol, evelien van geffen, angela buchholz, esther welp, erik van ameijden, and maria prins / trod ction: recent advances in health care and drug treatment have improved the health of populations with special social and health care needs, such as drug users. however, still a substantial number dots not have access to the type of services required to improve their health status. in the netherlands, tspccially young adult drug users (yad) whose primary drug is cocaine might have limited access to drugrreatment services. in this study we examined the history and current use of (drug associated) treatmmt services, the determinants for loss of contact, and the current health care needs in the young drug mm amsterdam study (yodam). methods: yodam started in and is embedded in the amsterdam cohort study among drug mm. data were derived from y ad aged < years who had used cocaine, heroin, ampheramines and i or methadone at least days a week during the months prior to enrolment. res lts:of yao, median age was years (range: - years), % was male and % had dutch nationality at enrolment. nearly all participants ( %) reported a history of contact with drug llt.lnnent services (methadone maintenance, rehabilitation clinics and judicial treatment), mental health car? (ambulant mental care and psychiatric hospital) or general treatment services (day-care, night-care, hdp for living arrangements, work and finance). however, only % reported contact in the past six l!xlllths. this figure was similar in the first and second follow-up visit. among y ad who reported no current contact with the health care system, % would like to have contact with general treatment serl' icts. among participants who have never had contact with drug treatment services, % used primarily cocaine compared with % and % among those who reported past or current contact, respectively. saied on the addiction severity index, % reported at least one mental health problem in the past days, but only % had current contact with mental health services. concl sion: results from this study among young adult drug users show that despite a high contact rm with health care providers, the health care system seems to lose contact with yao. since % indicatt the need of general treatment services, especially for arranging house and living conditions, health m services that effectively integrate general health care with drug treatment services and mental health care might be more successful to keep contact with young cocaine users. mtthods: respondents included adults aged and over who met dsm-iv diagn?snc criteria for an anxiety or depressive disorder in the past months. we performed two sets of logisnc regressmns. thtdichotomous dependent variables for each of the regressions indicated whether rhe respondenr_vis-ud a psychiatrist, psychologist, family physician or social worker in the _past_ months. no relationship for income. there was no significant interaction between educatmn an mco~:· r: ::or respondents with at least a high school education to seek help ~rom any of the four servic p were almost twice that for respondents who had not completed high school. th . d ec of analyses found che associacion becween educacion and use of md-provided care e secon s · · be d · · ·f· ly ·n che low income group for non-md care, the assoc anon cween e ucatlon and was s gm icant on -· . . . . use of social workers was significant in both income groups, but significant only for use of psychologists in che high-income group. . . . conclusion: we found differences in healch service use by education level. ind v duals who have nor compleced high school appeared co use less mental he~lt~ servi~es provided ~y psyc~iatrists, psycholo· gists, family physicians and social workers. we found limited e.v dence _suggesting the influence of educa· tion on service use varies according to income and type of service provider. results suggesc there may be a need to develop and evaluate progr~ms.designe~ to deliver targeted services to consumers who have noc completed high school. further quahtanve studies about the expen· ence of individuals with low education are needed to clarify whether education's relationship with ser· vice use is provider or consumer driven, and to disentangle the interrelated influences of income and education. system for homeless, hiv-infected patients in nyc? nancy sahler, chinazo cunningham, and kathryn anastos introduction: racial/ethnic disparities in access to health care have been consistently documented. one potential reason for disparities is that the cultural distance between minority patients and their providers discourage chese patients from seeking and continuing care. many institucions have incorporated cultural compecency craining and culturally sensicive models of health care delivery, hoping co encourage better relacionships becween patients and providers, more posicive views about the health care system, and, ulcimacely, improved health outcomes for minority patients. the current scudy tests whether cultural distance between physicians and patients, measured by racial discordance, predicts poorer patient attitudes about their providers and the health care system in a severely disadvantaged hiv-infected population in new york city that typically reports inconsistent patterns of health care. methods: we collected data from unscably housed black and latino/a people with hiv who reported having a regular health care provider. we asked them to report on their attitudes about their provider and the health care system using validated instruments. subjects were categorized as being racially "concordant" or "discordant" with their providers, and attitudes of these two groups were compared. results: the sample consisted of ( %) black and ( %) latino/a people, who reported having ( %) black physicians, ( %) latino/a physicians, ( %) white physicians, and ( %) physicians of another/unknown race/ethnicity. overall, ( %) subjects had physicians of a different race/ethnicity than their own. racial discordance did not predict negative attitudes about rela· tionship with providers: the mean rating of a i-item trust in provider scale (lo=high and o=low) was . for both concordant and discordant groups, and the mean score in -icem relationship with provider scale ( =high and !=low) was . for both groups. however discordance was significantly associated with distrust in che health care syscem: che mean score on a -icem scale ( =high discrust and l=low distrust) was . for discordant group and . for che concordant group (t= . , p= . ). we further explored these patterns separacely in black and lacino/a subgroups, and using different strategies ro conceptualize racial/ethic discordance. conclusions: in this sample of unscably housed black and latino/a people who receive hiv care in new york city, having a physician from the same racial/ethnic background may be less important for developing a positive doctor-patient relationship than for helping the patients to dispel fear and distrust about the health care system as a whole. we discuss the policy implications of these findings. ilene hyman and samuel noh . .abstract objectiw: this study examines patterns of mental healthcare utilization among ethiopian mm grants living in toronto. methods: a probability sample of ethiopian adults ( years and older) completed structured face-to-face interviews. variables ... define, especially who are non-health care providers. plan of analysis. results: approximately % of respondents received memal health services from mainstream healthcare providers and % consulted non-healthcare professionals. of those who sought mental health services from mainstream healthcare providers, . % saw family physicians, . % visited a psychiatrist. and . % consulted other healthcare providers. compared with males, a significantly higher proportion gsfer sessions v ri ftlnales consulted non-healthcare_ professionals for emotional or mental health problems (p< . ). tlbile ethiopian's overall use of mamstream healthcare services for emotional problems ( %) did not prlydiffer from the rate ( %) of the general population of ontario, only a small proportion ( . %) rjerhiopians with mental health needs used services from mainstream healthcare providers. of these, !oj% received family physicians' services, . % visited a psychiatrist, and . % consulted other healthll/c providers. our data also suggested that ethiopian immigrants were more likely to consult tradioooal healers than health professionals for emotional or mental health problems ( . % vs. . % ). our bivariate analyses found the number of somatic symptoms and stressful life events to be associated with an increased use of medical services and the presence of a mental disorder to be associated with a dfcreased use of medical services for emotional problems. however, using multivariate methods, only die number of somatic symptoms remained significantly associated with use of medical services for emooonal problems. diu#ssion: study findings suggest that there is a need for ethnic-specific and culturally-appropriate mrcrvention programs to help ethiopian immigrants and refugees with mental health needs. since there ~a strong association between somatic symptoms and the use family physicians' services, there appears robe a critical role for community-based family physicians to detect potential mental health problems among their ethiopian patients, and to provide appropriate treatment and/or referral. the authors acknowledge the centre of excellence for research in immigration and settlement (ceris) in toronto and canadian heritage who provided funding for the study. we also acknowledge linn clark whose editorial work has improved significantly the quality of this manuscript. we want to thank all the participants of the study, and the ethiopian community leaders without whose honest contributions the present study would have not been possible. this paper addresses the impact of the rationalization of health-care services on the clinical decision-making of emergency physicians in two urban hospital emergency departments in atlantic canada. using the combined strategies of observational analysis and in-depth interviewing, this study provides a qualitative understanding of how physicians and, by extension, patients are impacred by the increasing ancmpts to make health-care both more efficient and cost-effective. such attempts have resulted in significantly compromised access to primary care within the community. as a consequence, patients are, out of necessity, inappropriately relying upon emergency departments for primary care services as well as access to specialty services. within the hospital, rationalization has resulted in bed closures and severely rmricted access to in-patient services. emergency physicians and their patients are in a tenuous position having many needs but few resources. furthermore, in response to demands for greater accountability, physicians have also adopted rationality in the form of evidence-based medicine. ultimately, ho~ever, rationality whether imposed upon, or adopted by, the profession significantly undermines physu.: ans' ability to make decisions in the best interests of their patients. johnjasek, gretchen van wye, and bonnie kerker introduction: hispanics comprise an increasing proportion of th.e new york city (nyc) populanon !currently about %). like males in the general population, h spamc males (hm) have a lower prrval,nce of healthcare utilization than females. however, they face additional access barriers such as bnguage differences and high rates of uninsurance. they also bear a heavy burden of health problems lllehasobesity and hiv/aids. this paper examines patterns of healthcare access and ut hzat on by hm compared to other nyc adults and identifies key areas for intervention. . . . and older are significantly lower than the nhm popu anon . v. . , p<. ), though hi\' screening and immunizations are comparable between the two groups. conclusion: findings suggest that hm have less access t? healthcare than hf or nhm. hown r, hm ble to obtain certain discrete medical services as easily as other groups, perhapsdueto!rtor are a hm. i i . subsidized programs. for other services, utilization among s ower. mprovmg acc~tocareinthis group will help ensure routine, quality care, which can lead to a greater use of prevennve services iii! thus bener health outcomes. introduction: cancer registry is considered as one of the most important issues in cancer epidemiology and prevention. bias or under-reporting of cancer cases can affect the accuracy of the results of epidemiological studies and control programs. the aim of this study was to assess the reliability of the regional cancer report in a relatively small province (yasuj) with almost all facilities needed for c llcll diagnosis and treatment. methods: finding the total number of cancer cases we reviewed records of all patients diagnoicd with cancer (icd - ) and registered in any hospital or pathology centre from until i n yasuj and all ( ) surrounding provinces. results: of patients who were originally residents of yasui province, . % wereaccoulll!d for yasuj province. the proportion varies according to the type of cancer, for exarnplecancetsofdiglstive system, skin and breast were more frequently reported by yasuj's health facilities whereas cancmoi blood, brain and bone were mostly reported by neighbouring provinces. the remaining cases ( . % were diagnosed, treated and recorded by neighbouring provinces as their incident cases. this is partly because of the fact that patients seek medical services from other provinces as they believed that the facil. ities are offered by more experienced and higher quality stuffs and their relative's or temporary acooiii' modation addresses were reported as their place of residence. conclusion: measuring the spatial incidence of cancer according to the location of report ortht current address affected the spatial statistics of cancer. to correct this problem recording the permanm! address of diagnosed cases is important. p - (c). providing primary healthcare to a disadvantaged population at a university-run commumty healthcare facility tracey rickards the. c:ommuni~y .h~alth ~linic (chc) is a university sponsored nurse-managed primary bealthwt (p~c:l clime. the clm c is an innovative model of healthcare delivery in canada that has integrated tht principles of phc ser · · h' . vices wit ma community development framework. it serves to provide access to phc services for members of th · · illi · dru is ii be . . e community, particularly the poor and those who use or gs, we mg a service-learning facil'ty f d · · · · · · d rionll h . . .,m.:. · t · . meet c ient nee s. chmc nursing and social work staff and srudents r·--· ipa em various phc activities and h .l.hont" less i . f . outreac services in the local shelters and on the streels to'"" popu auon o fredericton as well th chc · model iii fosterin an on oi : . • e promotes and supports a harm reduction . · local d!or an~ h ng ~art:ersh p with aids new brunswick and their needle exchange program, w tha ing condoms and :xu:t h:~~~e e~aint~nance therapy clients, and with the clie~ts themselves ~_r; benefits of receiving health f ucation, a place to shower, and a small clothing and food oai~· care rom a nurse p · · d d · --""~'i"· are evidenced in th r research that involved needsaans mvo ves clients, staff, and students. to date the chc has unacn- · sessment/enviro i . d ; •• '"""" ll eva uanon. the clinic has also e . d nmenta scan, cost-benefit analysis, an on-go...,, "".'i'~ facility and compassionate lea x~mme the model of care delivery' focusing on nursing roles wi~ cj rmng among students. finally, the clinic strives to share the resu•p v . -arch with the community in which it provides service by distributing a bi-monthly newsletter, and plllicipating in in-services and educational sessions in a variety of situations. the plan for the future is coolinued research and the use of evidence-based practice in order to guide the staff in choosing how much n~ primary healthcare services to marginalized populations will be provided. n- (c) tuming up the volume: marginalized women's health concerns tckla hendrickson and betty jane richmond bdrotbu:tion: the marginalization of urban women due to socio-economic status and other determinants negatively affects their health and that of their families. this undermines the overall vitaliry of urban communities. for example, regarding access to primary health care, women of lower economic surus and education levels are less likely to be screened for breast and cervical cancer. what is not as widely reported is how marginalized urban women in ontario understand and articulate their lack of access to health care, how they attribute this, and the solutions that they offer. this paper reports on the rnults of the ontario women's health network (owhn) focus group project highlighting urban women's concerns and suggestions regarding access to health care. it also raises larger issues about urban health, dual-purpose focus group design, community-based research and health planning processes. mdhods: focus group methodology was used to facilitate a total of discussions with urban and rural women across ontario from to . the women were invited to participate by local women's and health agencies and represented a range of ages, incomes, and access issues. discussions focussed on women's current health concerns, access to health care, and information needs. results were analyzed using grounded theory. the focus groups departed from traditional focus group research goals and had two purposes: ) data collection and dissemination (representation of women's voices), and ) fostering closer social ties between women, local agencies, and owhn. the paper provides a discussion and rationale for a dual approach. rax/ts: the results confirm current research on women's health access in women's own voices: urban women report difficulty finding responsive doctors, accessing helpful information such as visual aids in doctors' offices, and prohibitive prescription costs, in contrast with rural women's key concern of finding a family doctor. the research suggests that women's health focus groups can address access issues by helping women to network and initiate collective solutions. the study shows that marginalized urban women are articulate about their health conctrns and those of their families, often understanding them in larger socio-economic frameworks; howtver, women need greater access to primary care and women-friendly information in more languages and in places that they go for other purposes. it is crucial that urban health planning processes consult directly with women as key health care managers, and turn up the volume on marginalized women's voices. women: an evaluation of awareness, attitudes and beliefs introduction: nigeria has one of the highest rates of human immunodeficiency virus ihivi seroprrvalence in the world. as in most developing countries vertical transmission from mother to child account for most hiv infection in nigerian children. the purpose of this study was ro. determine the awareness, attitudes and beliefs of pregnant nigerian women towards voluntary counseling and testing ivct! for hiv. mnbod: a pre-tested questionnaire was used to survey a cross section '.>f. pregnant women ~t (lrlleral antenatal clinics in awka, nigeria. data was reviewed based on willingness to ~c~ept or re ect vct and the reasons for disapproval. knowledge of hiv infection, routes of hiv transm ssmn and ant rnroviral therapy iart) was evaluated. hsults: % of the women had good knowledge of hiv, i % had fair knowledge while . % had poor knowledge of hiv infection. % of the women were not aware of the association of hreast milk feeding and transmission of hiv to their babies. majority of the women % approved v~t while % disapproved vct, % of those who approved said it was because vct could ~educe risk of rransmission of hiv to their babies. all respondents, % who accepted vc.i ~ere willing to be tnted if results are kept confidential only % accepted to be tested if vc.t results w. be s~ared w .th pinner and relatives % attributed their refusal to the effect it may have on their marriage whale '-gave the social 'and cultural stigmatization associated with hiv infection for their r~fusal.s % wall accept vct if they will be tested at the same time with their partners. ~ of ~omen wall pref~r to breast feed even if they tested positive to hiv. women with a higher education diploma were times v more likely to accept vct. knowledge of art for hiv infected pregnant women as a means of pre. vention of maternal to child transmission [pmtct) was generally poor, % of respondents wm aware of art in pregnancy. conclusion: the acceptance of vct by pregnant women seems to depend on their understanding that vct has proven benefits for their unborn child. socio-cultur al factors such as stigmatizationof hiv positive individuals appears to be the maj_or impedi~ent towards widespread acceptanee of ycr in nigeria. involvemen t of male partners may mpro~e attitudes t~wa~ds vct:the developmentofm novative health education strategies is essential to provide women with mformanon as regards the benefits of vct and other means of pmtct. p - (c) ethnic health care advisors in information centers on health care and welfare in four districts of amsterdam arlette hesselink, karien stronks, and arnoud verhoeff introduction : in amsterdam, migrants report a "worse actual health and a lower use of health care services than the native dutch population. this difference might be partly caused by problems migrants have with the dutch language and health care and welfare system. to support migrants finding their way through this system, in four districts in amsterdam information centers on health care and welfare were developed in which ethnic health care advisors were employed. their main task is to provide infor· mation to individuals or groups in order to bridge the gap between migrants and health care providers. methods: the implementat ion of the centers is evaluated using a process evaluation in order to give inside in the factors hampering and promoting the implementat ion. information is gathered using reports, attending meetings of local steering groups, and by semi-structu red interviews with persons (in)directly involved in the implementat ion of the centers. in addition, all individual and groupcontaets of the health care advisors are registered extensively. results: since four information centers, employing ethnic health care advisors, are implemented. the ethnicity of the health care advisors corresponds to the main migrant groups in the different districts (e.g. moroccan, turkeys, surinamese and african). depending on the local steering groups, the focus of the activities of the health care advisors in the centers varies. in total, around individual and group educational sessions have been registered since the start. most participants were positive about the individual and group sessions. the number of clients and type of questions asked depend highly on the location of the centers (e.g. as part of a welfare centre or as part of a housing corporation). in all districts implementa tion was hampered by lack of ongoing commitment of parties involved (e.g. health care providers, migrant organization s) and lack of integration with existing health care and welfare facilities. discussion: the migrant health advisors seem to have an important role in providing information on health and welfare to migrant clients, and therefore contribute in bridging the gap between migrants and professionals in health care and welfare. however, the lack of integration of the centers with the existing health care and welfare facilities in the different districts hampers further implementation . therefore, in most districts the information centres will be closed down as independent facilicities in the near future, and efforts are made to better connect the position of migrant health advisor in existing facilities. the who report ranks the philippines as ninth among countries with a high tb prevalence. about a fourth of the country's population is infected, with majority of cases coming from the lower socioeconomic segments of the community. metro manila is not only the economic and political capital of the philippines but also the site of major universities and educational institutions. initial interviews with the school's clinicians have established the need to come up with treatment guidelines and protocols for students and personnel when tb is diagnosed. these cases are often identified during annual physical examinations as part of the school's requirements. in many instances, students and personnel diagnosed with tb are referred to private physicians where they are often lost to follow-up and may have failure of treatment due to un monitored self-administered therapy. this practice ignores the school clinic's great potential as a tb treatment partner. through its single practice network (spn) initiative, the philippine tuberculosis initiatives for the private sector (philippine tips), has established a model wherein school clinics serve as satellite treatment partners of larger clinics in the delivery of the directly observed treatment, short course (dots) protocol. this "treatment at the source" allows school-based patients to get their free government-suppl ied tb medicines from the clinic each day. it also cancels out the difficulty in accessing medicines through the old model where the patient has to go to the larger clinic outside his/her school to get treatment. the model also enables the clinic to monitor the treatment progress of the student and assumes more responsibility over their health. this experience illustrates how social justice in health could be achieved from means other than fund generation. the harnessing of existing health service providers in urban communities through standardized models of treatment delivery increases the probability of treatment success, not only for tb but for other conditions as well. p - (c) voices for vulnerable populations: communalities across cbpr using qualitative methods martha ann carey, aja lesh, jo-ellen asbury, and mickey smith introduction: providing an opportunity to include, in all stages of health studies, the perspectives and experiences of vulnerable and marginalized populations is increasingly being recognized as a necessary component in uncovering new solutions to issues in health care. qualitative methods, especially focus groups, have been used to understand the perspectives and needs of community members and clinical staff in the development of program theory, process evaluation and refinement of interventions, and for understanding and interpreting results. however, little guidance is available for the optimal use of such information. methods: this presentation will draw on diverse experiences with children and their families in an asthma program in california, a preschool latino population in southern california, a small city afterschool prevention program for children in ohio, hiv/aids military personnel across all branches of the service in the united states, and methadone clinic clients in the south bronx in new york city. focus groups were used to elicit information from community members who would not usually have input into problem definitions and solutions. using a fairly common approach, thematic analysis as adapted from grounded theory, was used to identify concerns in each study. next we looked across these studies, in a meta-synthesis approach, to examine communalities in what was learned and in how information was used in program development and refinement. results: while the purposes and populations were diverse, and the type of concerns and the reporting of results varied, the conceptual framework that guided the planning and implementation of each study was similar, which led to a similar data analysis approach. we will briefly present the results of each study, and in more depth we will describe the communalities and how they were generated. conclusions: while some useful guidance for planning future studies of community based research was gained by looking across these diverse studies, it would be useful to pursue a broader examination of the range of populations and purposes to more fully develop guidance. background: the majority of studies examining the relationship between residential environments and cardiovascular disease have used census derived measures of neighborhood ses. there is a need to identify specific features of neighborhoods relevant to cardiovascular disease risk. we aim to ) develop methods· data on neighborhood conditions were collected from a telephone survey of s, fesi· dents in balth:.ore, md; forsyth county, nc; and new york, ny. a sample of of the i.ni~~l l'elpondents was re-interviewed - weeks after the initial interview t~ measure the tes~-~etest rebab ~ ty of ~e neighborhood scales. information was collected across seven ~e ghborho~ cond ~ons (aesth~~ ~uah~, walking environment, availability of healthy foods, safety, violence, social cohesion, and acnvmes with neighbors). neighborhoods were defined as census tracts or homogen~us census tra~ clusters. ~sycho metric properties.of the neighborhood scales were accessed by ca~cu~~.ng chronba~h s alpha~ (mtemal consistency) and intraclass correlation coefficients (test-r~test reliabilmes) .. pear~n s .corre~anons were calculated to test for associations between indicators of neighborhood ses (tncludmg d mens ons of race/ ethnic composition, family structure, housing, area crowding, residential stability, education, employment, occupation, and income/wealth) and our seven neighborhood scales. . chronbach's alphas ranged from . (walking environment) to . (violence). intraclass correlations ranged from . (waling environment) to . (safety) and wer~ high~~~ . ~ for ~urout of the seven neighborhood dimensions. our neighborhood scales (excluding achv hes with neighbors) were consistently correlated with commonly used census derived indicators of neighborhood ses. the results suggest that neighborhood attributes can be reliably measured. further development of such scales will improve our understanding of neighborhood conditions and their importance to health. childhood to young adulthood in a national u.s. sample jen jen chang lntrodfldion: prior studies indicate higher risk of substance use in children of depressed mothers, but no prior studies have followed up the offspring from childhood into adulthood to obtain more precise estimates of risk. this study aimed to examine the association between early exposure to maternal depl'elsive symptoms (mds) and offspring substance use across time in childhood, adolescence, and young adulthood. methods: data were obtained from the national longitudinal survey of youth. the study sample includes , mother-child/young adult dyads interviewed biennially between and with children aged to years old at baseline. data were gathered using a computer-assisted personal interview method. mds were measured in using the center for epidemiologic studies depression scale. offspring substance use was assessed biennially between and . logistic and passion regression models with generalized estimation equation approach was used for parameter estimates to account for possible correlations among repeated measures in a longitudinal study. rnlllta: most mothers in the study sample were whites ( %), urban residents ( %), had a mean age of years with at least a high school degree ( %). the mean child age at baseline was years old. offspring cigarette and alcohol use increased monotonically across childhood, adolescence, and young adulthood. differential risk of substance use by gender was observed. early exposure to mds was associated with increased risk of cigarette (adjusted odds ratio (aor) = . , % confidence interval ( ): . , . ) and marijuana use (aor = . , % ci: . , . ), but not with alcohol use across childhood, adolescence, and young adulthood, controlling for a child's characteristics, socioeconomic status, ~ligiosity, maternal drug use, and father's involvement. among the covariates, higher levels of father's mvolvement condluion: results from this study confirm previous suggestions that maternal depressive symptoms are associated with adverse child development. findings from the present study on early life experi-e~ce have the potential to inform valuable prevention programs for problem substance use before disturbances become severe and therefore, typically, much more difficult to ameliorate effectively. the ~act (~r-city men~ health study predicting filv/aids, club and other drug transi-b~) study a multi-level study aimed at determining the association between features of the urban enyjronment mental health, drug use, and risky sexual behaviors. the study is randomly sampling foster sessions v neighborhood residents and assessing the relations between characteristics of ethnographically defined urban neighborhoods and the health outcomes of interest. a limitation of existing systematic methods for evaluating the physical and social environments of urban neighborhoods is that they are expensive and time-consuming, therefore limiting the number of times such assessments can be conducted. this is particularly problematic for multi-year studies, where neighborhoods may change as a result of seasonality, gentrification, municipal projects, immigration and the like. therefore, we developed a simpler neighborhood assessment scale that systematically assessed the physical and social environment of urban neighborhoods. the impact neighborhood evaluation scale was developed based on existing and validated instruments, including the new york city housing and vacancy survey which is performed by the u.s. census bureau, and the nyc mayor's office of operations scorecard cleanliness program, and modified through pilot testing and cognitive testing with neighborhood residents. aspects of the physical environment assessed in the scale included physical decay, vacancy and construction, municipal investment and green space. aspects of the social environment measured include social disorder, social trust, affluence and formal and informal street economy. the scale assesses features of the neighborhood environment that are determined by personal (e.g., presence of dog feces), community (e.g., presence of a community garden), and municipal (e.g., street cleanliness) factors. the scale is administered systematically block-by-block in a neighborhood. trained research staff start at the northeast corner of an intersection and walk around the blocks in a clockwise direction. staff complete the scale for each street of the block, only evaluating the right side of the street. thus for each block, three or more assessments are completed. we are in the process of assessing psychometric properties of the instrument, including inter-rater reliability and internal consistency, and determining the minimum number of blocks or street segments that need to be assessed in order to provide an accurate estimate of the neighborhood environment. these data will be presented at the conference. obj«tive: to describe and analyze the perceptions of longterm injection drug users (idus) about their initiation into injecting. toronto. purposive sampling was used to seek out an ethnoculturally diverse sample of idus of both genders and from all areas of the city, through recruitment from harm reduction services and from referral by other study participants. interviews asked about drug use history including first use and first injecting, as well as questions about health issues, service utilization and needs. thematic analysis was used to examine initiation of drug use and of injection. results: two conditions appeared necessary for initiation of injection. one was a developed conception of drugs and their (desirable) effects, as suggested by the work of becker for marijuana. thus virtually all panicipants had used drugs by other routes prior to injecting, and had developed expectations about effects they considered pleasureable or beneficial. the second condition was a group and social context in which such use arose. no participants perceived their initiation to injecting as involving peer pressure. rather they suggested that they sought out peers with a similar social situation and interest in using drugs. observing injection by others often served as a means to initiate injection. injection served symbolic purposes for some participants, enhancing their status in their group and marking a transition to a different social world. concl ion: better understanding of social and contextual factors motivating drug users who initiate injection can assist in prevention efforts. ma!onty of them had higher educational level ( %-highschool or higher).about . yo adffiltted to have history of alcohol & another . % had history of smoking. only . % people were on hrt & . % were receiving steroid. majority of them ( . ) did not have history of osteoporosis. . % have difficulty in ambulating. only . % had family history of osteoporosis. bmd measurements as me~sured by dual xray absorptiometry (dexa) were used for the analysis. bmd results were compare~ w ~ rbc folate & serum vitamin b levels. no statistical significance found between bmd & serum v taffiln b level but high levels of folate level is associated with normal bmd in bivariate and multivariate analysis. conclusion: in the studied elderly population, there was no relationship between bmd and vitamin b ; but there was a significant association between folate levels & bmd. introduction: adolescence is a critical period for identity formation. western studies have investigated the relationship of identity to adolescent well-being. special emphasis has been placed on the influence of ethnic identity on health, especially among forced migrants in different foreign countries. methodology: this study asses by the means of an open ended question identity categorization among youth in three economically disadvantaged urban communities in beirut, the capital of lebanon. these three communities have different histories of displacement and different socio-demographic makeup. however, they share a history of displacement due to war. results and conclusion: the results indicated that nationality was the major category of identification in all three communities followed by origin and religion. however, the percentages that self-identify by particular identity categories were significantly different among youth in the three communities, perhaps reflecting different context in which they have grown up. mechanical heart valve replacement amanda hu, chi-ming chow, diem dao, lee errett, and mary keith introduction: patients with mechanical heart valves must follow lifelong warfarin therapy. war· farin, however, is a difficult drug to take because it has a narrow therapeutic window with potential seri· ous side effects. successful anticoagulation therapy is dependent upon the patient's knowledge of this drug; however, little is known regarding the determinants of such knowledge. the purpose of this study was to determine the influence of socioeconomic status on patients' knowledge of warfarin therapy. methods: a telephone survey was conducted among patients to months following mechan· ical heart valve replacement. a previously validated -item questionnaire was used to measure the patient's knowledge of warfarin, its side effects, and vitamin k food sources. demographic information, socioeconomic status data, and medical education information were also collected. results: sixty-one percent of participants had scores indicative of insufficient knowledge of warfarin therapy (score :s; %). age was negatively related to warfarin knowledge scores (r= . , p = . ). in univariate analysis, patients with family incomes greater than $ , , who had greater. than a grade education and who were employed or self employed had significantly higher warfarm knowledge scores (p= . , p= . and p= . respectively). gender, ethnicity, and warfar~n therapy prior to surgery were not related to warfarin knowledge scores. furthermore, none of t~e. m-hospital tea~hing practices significantly influenced warfarin knowledge scores. however, panic ~ants who _rece v~d post discharge co~unity counseling had significantly higher knowledge scores tn comp~r son with those who did not (p= . ). multivariate regression analysis revealed that und~r~tandmg the ~oncept of ?ternational normalized ratio (inr), knowing the acronym, age and receiving ~ommum !' counseling after discharge were the strongest predictors of warfarin kn~wledge. s~ oeconom c status was not an important predictor of knowledge scores on the multivanate analysis. poster sessions v ~the majority of patients at our institution have insufficient knowledge of warfarin therapy.post-discharge counseling, not socioeconomic status, was found to be an important predictor of warfarin knowledge. since improved knowledge has been associated with improved compliance and control, our findings support the need to develop a comprehensive post-discharge education program or, at least, to ensure that patients have access to a community counselor to compliment the in-hospital educatiop program. brenda stade, tony barozzino, lorna bartholomew, and michael sgro lnttotl#ction: due to the paucity of prospective studies conducted and the inconsistency of results, the effects of prenatal cocaine exposure on functional abilities during childhood remain unclear. unlike the diagnosis of fetal alcohol spectrum disorder, a presentation of prenatal cocaine exposure and developmental and cognitive disabilities does not meet the criteria for specialized services. implications for public policy and services are substantial. objective: to describe the characteristics of children exposed to cocaine during gestation who present to an inner city specialty clinic. mnbods: prospective cohort research design. sample and setting: children ages to years old, referred to an inner city prenatal substance exposure clinic since november, . data collection: data on consecutive children seen in the clinic were collected over an month period. instrument: a thirteen ( ) page intake and diagnostic form, and a detailed physical examination were used to collect data on prenatal substance history, school history, behavioral problems, neuro-psychological profile, growth and physical health of each of the participants. data analysis: content analysis of the data obtained was conducted. results: twenty children aged to years (mean= . years) participated in the study. all participants had a significant history of cocaine exposure and none had maternal history or laboratory (urine, meconium or hair) exposure to alcohol or other substances. none met the criteria of fetal alcohol spectrum disorder. all were greater than the tenth percentile on height, weight, and head circumference, and were physically healthy. twelve of the children had iqs at the th percentile or less. for all of the children, keeping up with age appropriate peers was an ongoing challenge because of problems in attention, motivation, motor control, sensory integration and expressive language. seventy-four percent of participants had significant behavioral and/or psychological problems including aggressiveness, hyperactivity, lying, poor peer relationships, extreme anxiety, phobias, and poor self-esteem. conclusion: pilot study results demonstrated that children prenatally exposed to cocaine have significant learning, behavioural, and social problems. further research focusing on the characteristics of children prenatally exposed to cocaine has the potential for changing policy and improving services for this population. methods: trained interviewers conducted anonymous quantitative surveys with a random sample (n= ) of female detainees upon providing informed consent. the survey focused on: sociodemographic background; health status; housing and neighborhood stability and social resource availability upon release. results: participants were % african-american, % white, % mixed race and % native american. participants' median age was , the reported median income was <s , year, and % reported receiving a high school diploma or equivalent. women reported a number of health conditions rypical of underserved populations, including asthma ( %), sexually transmitted infections ( %), high blood pressure ( %), hcv ( %), diabetes ( %) and hiv ( %). nearly half ( %) did not anticipate having a place to stay for at least days upon release. factors significantly associated housing stability upon release were: high family support score (adjusted odds ratio [aor) . ; % confidence interval ( % cl) . , . ), high neighborhood stability score (aor . ; % cl . , . ), wanting a commercial sex worker (csw) support group (aor . ; % cl . , . ); and identifying as bisexual (aor . ; % cl . , . ). women desired employment ( %), housing ( %), education ( %), drug treattnent ( %), help with custody of children ( %), childcare ( %), and domestic violence suppon ( %) services. conclusions: female detainees represent one of urban centers' most marginalized pcjpwatioos. short periods of detention represent a unique opportunity for _interven?~ns bri~ co~s and public health institutions. service providers should collaborate ~ th local ~ails to .p~de a con uwnof care for female detainees upon release that includes transportation , housing, residential drug treallllcnt, employment, education, family reunification, childcare and domestic viol~nce su~rt. ~pecial attenlion is warranted to lesbian and bisexual women and csws, who may be especially margmalized &om family and service-based support networks. introduction: "health care and ethnic minority immigrants" examines how health care policy dil· ferences between canada and the united states impact the health-related hardships, access and use of preventative care, and health outcomes of urban ethnic minority immigrants in both countries. methods: the findings of this paper build on the results of my qualitative comparative study of hotel workers in vancouver, bc and seattle, wa that revealed greater health related hardships for similarly matched employees in seattle compared to vancouver. in this paper, i examine the generalizability of these findings at the cross-national level for similar ethnic minority immigrant groups. i compare the impact of health care policy differences on specific groups that have emigrated to cities in both canada and the united states. these include immigrants from china, viemam, philippines, west indies, africa, sri lanka, pakistan, and latin america. comparative statistical analysis -utilizing rel· evant data from statistics canada and the u.s. census -reveal the extent to which health policy differ· ences help explain how current health policy in the united states disadvantages urban ethnic minority immigrants. results: many ethnic minority immigrants are a part of the working poor, a group which disproportionately lacks health insurance coverage in the united states. their position in the labour market makes them most vulnerable to exclusion from health care services. the data reveals how current u.s. health policy creates barriers for recently arrived ethnic minority immigrants to access health insurance and care. it remains difficult to ascribe health outcome differences directly to policy differences because of the challenge in disentangling the complex interacting interventing variables, including income inequality, that determine health outcomes. yer suggestive evidence suggests that health policy in the united states is harming the health of urban ethnic minority immigrants. the current health policy regime in the united states harms the health access, care, and outcomes of urban ethnic minority immigrants. comparing the fortunes of similar immigrants in cana· dian and u.s. cities reveals these patterns of disadvantage and some of their consequences. these barriers are an understudied factor in the sociological literature on "segmented assimilation" and social exclu· sion. the paper ends with policy recommendatio ns to improve access to health care among ethnic minor· ity immigrants in both countries, with the goal of reducing health related hardships, and improving health outcomes. mass index deyu pan, richard baker, and keith norris badtgrou~ over the past decades, there has been dramatic increase in prevalence of obesity in the us population. however, the relationship between obesity and the prevalence of cardiovascular dis· ease (cv~) risk factors in different race/ethnic groups over time is not well known. . ik~rgn: _we use cross-sectional , nationally representative surveys: national health and nutri· t nal examination survey (nhanes iii - (n= ) and nhanes nhanes - , including white, black, and hispa~ic races who were no~preg~ant, aged to years. res lt : the preval~nce of high cholesterol level (~ mg/dl), untreated high blood pressure ( : l / mm hg) an~ diabetes were calculated according to bmi group (lean, < ; overweight, - ; and obese, : ) for different race/ethnicity groups. over the approximately years period (from l ~ ~o [ ] [ ] [ ] [ ] , reducrion in cvd risk factors in non-hispanic white has been observed. for mmonty race/~hnicity groups, black and hispanic, there had been increases in prevalence in high blood fa pressure and diabetes. the lean group experienced larger increase in prevalence of those cvd risk ctors. . fo~~ the prevalence in cvd risk factors over time had reduced in most of the bmi ca egoes r t e w ~~e population. however, for black and hispanic, prevalence of of cvd risk factors ave generauy uncreased, especially in overweight and obese groups. methods: strategies identified to achieve these goals include: developing meaningful neighbourhood and district boundaries for comparing health information, providing free access to neighbourhood health profiles (including relevant data at the smallest level for which valid rates could be calculated); mapping relationships of inequality at a variety of nested levels; providing a range of formats (maps, tables) to meet the needs of users; providing technical support; seeking user input to advance and improve the site; and conducting workshops to foster access and use of data for decision-making , advocacy and collaboration. an evaluation strategy is being developed to assess the efforts and impact of these strategies. a preliminary assessment of the results of the first six months of activity will be completed in october . results: significant differences in health are shown at all the geographic levels indicating success in developing the boundaries. results tabulated for the first six months use of the site include: site visits; media use; reference/acknow ledgement of the site in other documents; number of contacts through presentations and workshops; feedback from users identifying strengths and limitations; and, response from health decision makers. members of the partnership are identifying additional tools and services to further support actions that reduce health inequalities. the assessment will be used to develop more specific goals, targets and monitoring mechanisms. conclusions: our experience with paper-based health profiles indicates that they have been used extensively for program planning and advocacy. the greater availability of information in a publiclyavailable web-based format is expected to translate into even greater usefulness and wider application. the web site has had considerable usage to date, extensive media coverage. site users and workshop participants have provided positive feedback and suggestions for next steps. the six month review will be available in october . in india, more than and a half people are hiv-positive and half a million have aids. india currently has the largest number of positive people in the world, oumumbering south africa and accounting for nearly one tenth of the global hiv/aids prevalence. the world bank predicts that by , there will be million hiv/aids cases in india. the central challenge facing hiv prevention efforts in south asia today is learning how to respond to the societal determinants of vulnerability to hiv. hiv/aids is an issue largely engulfed by social stigma. stigma and discrimination are often considered the foremost barriers to effective poster sess ns v prevention and care initiatives. stigma can make a person afraid of disclosing their status~ ~yone el se, and may make them feel depressed or alone. stigma can .also le~d to poor adherence to medicanon, ~ likelihood to access health and social services, and less desire to hve. hiv+ men and women may beafraidtotd! their co-workers that they have hiv for fear of their reactions or for fear of losing their jobs. in a study conducted of people living with hiv/aids in delhi, india ov~r. -~, many respo~ts shared their experiences of discrimination in their families, in their communmes, an~ m health ~e settmgs. these findings will be shared in the workshop, and will be compa~ed to m~ ex~nences workmg as an ~ co~l~ at the center for aids prevention studies in san francisco, cahforma and congreso de lannos unidos m philadelphia, pennsylvania. the workshop will include an overview of hiv/aids in urban contexts in tht united states (los angeles, san francisco, new york, philadelphia) and south asia (delhi, hyderabad, chennai). differences in methods for outreach, prevention and treatment efforts between devdoped world and developing world contexts will be discussed. a large portion of the workshop will be centered on discussion. participants will engage in an exercise to categorize their ideas of stigma. the workshop will also include a powerpoint presentation on the quantitative data gathered from the survey. the number of homeless and runaway youth is increasing in toronto, which is currently home to out of youth in the gt a who live alone, and it is the preferred locale for the street-involved and homeless youth. the city's youth population is expected to grow by nearly % by , the school dropout rate is rising, and there are is a paucity of empirical data on what works with these at-risk youth. over a two-year period, ( ) ( ) ( ) , youthlink-inner city, conducted an evaluation of the impact of a harm reduction program aimed at reducing street youth's risk of contracting/infecting others with the hep c virus, which has both short-term and long-term deleterious effects. demographic data from street-youth, along with resources/services used, employment methods, type and frequency of drug use, health status, police contacts, and their views of program impact were analyzed using a standardized sur· vey. additionally, focus groups with youth, agency staff and community key informants were conducted, as well as in-depth interviews with three youth, over a sixth-month period. this paper details study results, which both inform both practice and future study about what works, why it works, and how best to work with these vulnerable youth. sho~ed .that the wasteland in this area was contaminated by as cd zn pb cu simultaneously. the con-ta~matton of as ~d was quit significant. the contamination problems and environmental issues in this region are very. serious. the awareness on environmental and health issues was investigated by spot survey and analysis. overall awareness among the residents in the region is very poor. the measures must be taken to assu~e t~e .sustainable economy development by local and central gorvernments. keywords nandan guangx ; mmmg area; environmental awareness. concern like, epileptic fits, vision problems, earache, cough of more than weeks and urinary problems. ninety-five subjects did not take bath regularly and were exposed to sex. the health problems identified are only of a particular point of time and it may be difficult to interpret the depth of "iceberg" of the street children's world also draw the health-illness continuum. periodic interaction and follow-up is very difficult as they generally disappear from the research setting due to their frequent mobility for survival measures. as per the prediction of the iceberg theory, only some problems may have been identified, larger problems in respect to their health may not have been identified. in spite of various limitations, this attempt had proven that, it is possible to enter the street children world, explore the iceberg of illnesses, and establish data of health-illness continuum through an effective nursing agency. it is recommended to deworm these children, provide nutritional education, establish "condom corners" and "street children help line" in the city and urban slum areas and undertake action research on their health. malnutrition is a serious problem in developing countries like bangladesh. malnutrition causes a great deal of child suffering. malnutrition is one of the major causes of morbidity and mortality among the child. the aim of present study was to investigate the nutritional status and its relation to socioeconomic conditions of urban disadvantaged child of under five years age. nutritional status was determined by anthropoemetric measurement(heig ht, weight, mid-arm circumference etc.). determination of total protein and serum albumin were done for biochemical examination. haematological examination was done by blood haemoglobin profile estimation by cynmethhaemoglob in method and determination of haematocrit value or packed cell volume (pcv). stool examination for ova of hook worm, round worm, trichuris species and other species were also done. relevant information on socioeconomic characteristics was recorded by interviewing the house hold head using pretested questionnaire. our study demonstrated that nutritional status of the children are positively correlated with family income, parents level of formal education and negatively related to the family size. the effect of family income on the nutritional status, haematological and biochemical indices of urban disadvantaged child under five will be discussed in detail which will help us to determine proper way of utilization of health care facilities exists in developing countries. introduction: with the increase in morbidity and reduction in mortality and with the introduction of highly active antiretroviral therapy (haart), there is increasing focus on the determinants of healthrelated quality of life (hrqol) in hiv-infection. the focus on the present study is to examine the relationship between social support, depression, and hiv disease severity, and the extent to which these variables impact on hrqol in adult men with hiv-infection. methods: as part of a larger ongoing natural history study focusing on the neurobehavioural complications of hiv and aids, we administered questionnaires to assess depression (beck depression inventory), social support, and hrqol (mos-hiv) to adult men with hiv-infection. a structured interview was used to collect health information and data on hiv disease severity. physical and mental health summary scores (phs and mhs) were derived through principal components analysis. participants were grouped according to level of social support: "well supported" (n= ), "moderately supported" (n= ), "little or ineffective support" (n= ). analysis of variance was conducted to assess the effects of three levels of perceived social support, depression status (present vs absent), and hiv disease severity (aids vs non-aids) on mental and physical health dimensions of hrqol. potential interaction effects were also evaluated. results: social support was found to have a significant effect on both mhs and phs. presence of depression was found to have a significant effect on mhs but not phs. hiv disease severity (presence of aids diagnosis) was found to have a significant effect on phs but not mhs. manov a analyses revealed no significant interactions effects. conclusions and implications: level of social support, presence of depression and hiv disease severity were shown to have independent effects on hrqol. feeling "well supported" appears to have significant benefits for mental and physical health. biological indicators of hiv disease appear to have a selective impact on physical health while presence of depression is related to significant reductions in mental health. the development and evaluation of behavioural interventions to improve perceived social support network and depression will likely result in significant improvements in health outcomes of adults with hiv and aids. introduction: ongoing medical advances have greatly enhanced the longevity of penons living with aids (plwa). however, for certain subgroups living with hiv/aids, including, members of minority groups, women and the economically underprivilege d, aids outcomes have not changed so favorably. one obvious factor to consider when explaining disparities in aids outcomes is the environ· ment within which an individual resides. few studies of aids outcomes have focused on how commu· nity setting influences the effectiveness of care delivery. the principle research questions were: ) what is the relationship between the locations of areas with concentrations of pl wa and the distribution of both primary and ancillary service providers? ) how has the widespread availability of haart (after ) impacted aids outcomes at the community level? ) how do aids mortality and fatality rates vary when related community characteristics, such as household income, ethnic mix, and geographic access to primary and ancillary hiv/aids services are considered? we examine this issue across residential communities in the los angeles area. methods: los angeles county's comprehensive aids service providers database (compiled and maintained by aids project los angeles) was geo-referenced and distances between weighted mean population centers and the nearest hiv/aids service providers were calculated to provide a measure of access which was then merged with aids diagnosis and mortality data along with relevant socioeconomic and population indicators and for analysis using bivariate and multivariate statistics at the zip code level. results: there is a growing disparity in hiv/aids outcomes between low-income minority areas and affluent non-minority areas in the post-haart era (p = . ). ancillary aids services such as case management and counseling and testing are located near the places where low income hiv/aids service consumers are likely to live (p =. ). in spite of having more access to ancillary services low income areas continue to be associated with smaller decreases post-haart aids mortality rates (p= . ). conclusions: given the increasing disparities in aids outcomes between lower and upper income communities in the post -haart era, more specific research into the capacities of aids services providers and the efficiency of their interventions is required. although it is clear that ancillary services are operating in the areas of greatest need, their effectiveness remains limited. understanding the reasons for t~is, be they lack of adequate resources for inner city service providers, failure to reach target popula· tmns or other causes, requires additional research. in ? , y.out~ who were able to speak either french or english and had been absent from their parent's/ c~regivers ~es. dence for at least three consecutive nights took part in the survey which consisted of inter· viewer-adm ms tered question~aires. p.arti~i~an~s were recruited from drop in centres in cities across <?-nada.y~uth self-report as either using in ect on or non-injection drugs. statistical analyses were car· r ed out using sas version . the 'home' is a contested site for many women living in urban areas. women living in poverty and using illicit drugs are largely excluded from participation in dominant 'home-base' gender roles of wife and mother because of economic disadvantage. they thus 'make home' in ways that are specific to their everyday experiences. while research has established links between housing, health and drug use, this literature does not tend to consider the meanings that home may have within the lives of women who lack access to adequate tenured living spaces. this presentation reports the findings of my master's thesis work. using grounded theory methodology within a poststructuralist feminist conceptual framework, i conducted in-depth, open-ended interviews with women living in the toronto area. the women were recruited from within the community through posters at different social service agencies (e.g., drop-in centres, community health centres). they were asked to describe their housing experiences and what home meant to them over the course of their lives. through the data analysis process, a substantive theory of 'making home' for women living in poverty and using illicit drugs emerged. the central concept of making home is a continual process of learning about and interacting with the environment. the process of making home entails different subprocesses: finding home (knowing what is available and accessible, and accessing home), adaptation, and leaving home. the different meanings of home that women developed from their experiences and knowledge emerged as critical components for the process of making home. the women i interviewed were very mobile and experienced constant change with regards to home. home was not considered only in relation to physical living space. home could be made within a relationship or with regards to a possession. while dominant meanings of home relation to tenured living spaces are generally positive, my research indicated that home could also be a negative context. the presentation will describe my research process and findings as well as the theoretical and policy implications of my results. in the western democracies, social citizenship bundles the right to social provision (defined as a share of the social good, not necessarily proportionate to the market value of a citizen's contribution) with participation in the paid labour force. for this reason, social citizenship rights, which usually involve some kind of redistributive measures, are a key mechanism by which states ensure economic equality, or at least, economic equality of opportunity, but are also a mechanism of social exclusion. social rights are inscribed around a single kind of relationship, that which exists between a male family breadwinner and the paid labor market; those who make economic contributions that fall outside this relationship -such as unpaid care-work, or, work that occurs in shadow or underground economiesare to a greater or lesser degree barred from accessing citizen-based social provisions. furthermore, social provision that occurs outside of the breadwinner/market-eco nomy dyad is very often meanstested and is accompanied by regulatory state apparatuses (this includes a range of social services, from welfare payments, to child-care subsidies, to disability pensions). social citizenship is thus stratified; the legal relationship that is at the heart of social citizenship acts as a form of social closure against claims for a share of the social good made by those who are 'lesser' citizens than others. of particular interest in this paper is how citizenship inequalities translate into inequalities in the social provisions that emerge from economic participation: the right to safety on the job, protection from employer harassment, protection from the vagaries of the market as well the right to adequate, comprehensive, and appropriate health services. drawing on mixed methods, longitudinal data from adult sex workers (n= ) located in two research sites with different social welfare regimes -one in canada and one in the u.s. -we examine the consequences of working in a "shadow" or "underground" economy on various facets of health and access to health services, taking into consideration the mediating role that citizenship constructs and social welfare regimes play in accessing other key social and economic determinants of health. methods: the study population included methadone patients (re)admitted at the mhs in the period from / / to / / , born in the netherlands, morocco, surinam, dutch antilles or turkye, and officially registered in the population register of amsterdam. the population register was used to ascer· rain the vital status. causes of death were provided by the central bureau of statistics. mortality was categorised as hiv related, directly drug related (overdose) and other.mortality. results: the methadone patients had the following characteristics: years of age at entry; % male; % ethnic minority; % ever injected. in total, personyear (py) of observation time and deaths ( % hiv related, % overdose; % other) were observed. hence, the crude mortality rate was / py ( % ci - / py). the percentage of (ever) injectors was higher among the native dutch than among the ethnic minorities, % and % respectively. higher rates were observed among native dutch drug users compared to those belonging to an ethnic minority (age adjusted hazard ratio (hr) . ( % ci . - . ). the age adjusted hr of (ever) injecting drug users versus non injecting users was . ( % cl . - . ). after additional adjustment for route of administration a non significant difference between the dutch and ethnic minorities remained (hr . , % cl . - . , p-value . . conclusion: the mortality rate among the heroin users in amsterdam is strongly affected by the high prevalence of non-injecting drug use. moreover, this study confirms that differences in mortality between the native dutch and the ethnic minorities is related to differences in route of administration. the ongoing reduction of injecting drug use (due tot selctieve mortality, and switching route ofadministration and popularity of crack cocaine) may lead to a further reduction of mortality rates among heroin users in amsterdam. interventions preventing the initiation of injecting should be encouraged. . introduction: food insecurity is an inequality that is central in the lives of many low-income cana· d ans. people lack food security when regular access to nutritious food is limited or variable due to high prices'. low income, lack of transportation or inadequate food distribution, or they become disadvan· taged m other w~ys through the acquisition of food. a group comprising academics, health profession· als, and commumty workers who have experience in food insecurity, developed a pilot study in ottawa that sought to und~rstand the lived experience of food insecurity. the study also used the united states department of agriculture (usda) community food security module. methods: a series of group meetings determined the best research approaches; questionnaires and consent forms were developed by a working group. twenty-three self-identified food insecure respon· dents were interviewed. the data were analysed using frequency distributions· the food security module was coded according to the usda coding guide, and open-ended responses w~re coded using a grounded approach. renlts: preliminary results from our pilot study have given the research team cause for considerable concern. out of households without children, experienced food insecurity with hunger; ~ere at the severe l~vel. out of households with children, experienced food insecurity with hunger. ~•rst person reflecnons commonly featured feelings of depression low self-esteem and despair. participants' account tha d . an cu ty gettmg to the store, severely limited putting knowledge and skills mto practice. l'oster sessions v conclusion: based on these early findings, our research team is looking to challenge what appear to be assumptions about poverty and food insecurity and for best ways to use this information. some policy approaches and interventions that encourage people to eat better and exercise more, may be missing the mark for low-income individuals, and may serve to maintain food insecurity. future research will build on this pilot. with methods augmentation, and a comprehensive knowledge dissemination plan, we hope co contribute to research and policy frameworks at all levels. ps- (a) mental health and the corrections system: population-based analyses in urban, semi-urban, and rural settings julian somers, robert watts, and michelle patterson introduction: according to recent epidemiological research, rates of mental disorders vary considerably across countries and across regions within countries. nevertheless, rates of mental disorders (including substance use disorders) are consistently higher in populations involved in the corrections sys- em. courts have long recognized the heavy burden of mental illness within their purview, and have developed innovative programs to better manage the needs of such individuals. the majority of these innovations (e.g., specialized courts) exist in urban settings. however, few studies have examined the degree of variability in rates of different mental disorders between courts in urban and other settings (e.g., semi-urban, rural). variability between courts in different settings, if present, holds implications for needs-based resource planning. the present study was conducted as part of a long-term inter-ministerial collaboration in british columbia (bc). analyses were conducted on linked administrative data regarding population health and correctional services. a database was constructed including all individuals sentenced in bc in a single year (n= , ). corrections records were matched to records of health services utilization (hospital and outpatient services) for mental disorders and substance use disorders in the years preceding sentencing. services for mental health and substance-related problems were aggregated into three groups: severe mental illness (smi); less-severe mental illness (lsmi); alcohol/other drug (ad). courts were grouped, based on their annual volumes, inro three categories: "urban"; "semi-urban" and "rural." rates of service use for mental disorders were compared between groups for -year and -years preceding sentencing. results: there were significant differences in the rates of mental disorders in courts of different size (urban, semi-urban, rural) . however, differences between the rates of disorders within each of these groups exceeded the discrepancies between groups. comparatively high and low rates of disorders were observed in courts of each size. moreover, the courts with the highest rates of certain disorders (e.g., ad) did not have the highest rates of other types of mental disorders (e.g., smi). conclusions: rates of mental disorders differed significantly among the annual populations sentenced across courts in bc. urban courts (which process comparatively large numbers of people) have implemented services to address the needs of the mentally ill. the present analyses strongly suggest that program development should be closely linked to the demonstration of need. the results caution that a uniform approach to court programs for the mentally ill is likely to be inefficient, over-supplying services in some settings and underestimating need in others. results: public settings used for injection are characterized by highly unhygienic conditions, the presence of unsafely disposed syringes, limited availability of sterile syringes and a lack of sterile water for injecting. a number of unsafe injection practices observed were common among public injectors. the presence of police officers nearby and the potential of assault by street predators fostered rushed injecting among those consuming drugs in public spaces. the ecological features of these environments encourage unhygienic and unsafe injecting practices, heighten risk for overdose and the transmission of blood borne viruses. introduction: approximately % of women experience depression in the first weeks or months after giving birth. although it has been argued that postpartum depression (ppd) is a culture-bound p~ nomenon, experienced only in western, industrialized countries, recent international research studies have confirmed that the prevalence of ppd is similar around the world. however, little is known about variables that may influence the experience of ppd in women from diverse cultures and immigrant women. research is needed to identify the role culture may play in the presentation of ppd (i.e., types of symptoms most commonly reported), how women from various racial, ethnic and cultural backgrounds perceive and attribute their symptoms of ppd, and finally, how culture can be appropriately addressed in ppd treatment programs. method: to examine the role of culture in ppd, semi-structured interviews and self-report question· naires were administered to clients of the women's health centre of st. joseph's health centre, tor· onto. participants were identified as either first generation canadians (relative newcomen) (n= ) or second generation canadian (parents were immigrants to canada) (n= ). data were collected qd these two groups of women based on: severity of depression, symptom presentation, perceived role of social supports and culturally-specific traditions, and barriers and responses to treatment. the interview data were analyzed using qualitative methods (thematic content analysis), and the following themes were identified: ) stress about passing on their culture to their children, ) lack of social support and feelings of isolation, ) perceived importance or lack of importance of cultural based tra· ditions, ) conflicts with family members. about cultural traditions and beliefs, ) mental health stigma within ethnic communities and beyond, ) race-and sex-based discrimination, and ) language barriers. conclrllion: identifying the role culture plays in the presentation of ppd, and how women from diverse backgrounds perceive and attribute their symptoms of ppd, is critical in order to establishcultur· ally appropriate guidelines for treatment options. furthermore, information gathered from this study can be used to develop policies and resources for delivering culturally competent care for newcomer wo~ who are dealing with ppd as well as the issues around acculturation (i.e., language barriers, racism). llus is of particular importance for urban health centers which provide postpartum care to diverse groups of women, and particularly recent immigrants or newcomers. ps-~ (al. contaminated 'therapeutic landscape': perceptions of the aamjiwnaang fint nation keyln smith and isaac luginaah . in~: this. paper pres;ents the findings of an ongoing study among the aamjiwnaang f!rst nanon. aam wnaang is located m the heart of samia's 'chemical valley', surrounded by cherrucal ~(ants such as esso, imperial oil, shell, suncor energy, and canada's largest hazardous waste disposal sate. safety kleen. this fint nation community is located within the st. clair river •area of concem'. as destgna~ by health canada for the population of samia and the surrounding region. although this comm_umty, by way of. its proximity to the numerous chemical plants is already exposed to high levels pollu~on, recent che?ucal dumping in ~mjiwnaang, as well as a failed proposal for another ethanol plant m the community, only helped to mtensify community concerns about potential health impacts of exposure. research on the cultural beliefs and traditions of first nation communities has established that th~ ~isting rel~tionship between first nations people and 'mother earth' is not only physical, but also_ spmtual. in this study we explore how the complex relationship between the aamjiwnaang first naaon and 'mother earth' be ha · · · i .. may c ngmg a contammated 'therapeutic' landscape. the study a so ~lores h?w aam wnaang residents are coping with these changes and with the probable conramina· boa of their community. ra!jts: aamjiwnaang residents acknowledge that they are living in a contaminated environment and are being impacted by emissions from the surrounding 'chemical valley' especially for future generations, and have expressed concerns that members of the community and mother earth are 'sick' as a result of this exposure. while moving from that 'place' has been discussed, residents have strong personal and generational connections to the land and insist however, that aamjiwnaang is their 'home' and will remain that way despite growing community concerns about the impact from industry. the contribution of this study lies in the direct involvement of community leadership in designing and conducting this research and distributing the results to further local policy development regarding community concerns on the reserve. background: truck driver are at very high risk for drug abuse because the factor contributing to drug abuse among driver are multiple. it is important to gain an understanding of the key factors that contributing to drug abuse among truck drivers. methods: seventy-truck driver aged - years were conveniently selected from the population. all the participants were male. an interview schedule was developed in the light of literature data and data were collected by personal interview with informed consent in selected urban area of eastern part of nepal. results: a considerable percentage of truck driver have less knowledge about drug abuse, its effect on body and their complication. majority of the participants ( %) explained that lack of education, financial crisis were leading factors of drug abuse. the average numbers of respondents were believed that lack of meaning in life, marital disharmony. friendship with drug abuser, stress, tiredness, modernization of life pattern and freedom from the home pressure were the influencing risk factors to drug abuse. conchuion: this study reveals those truck drivers are at risk in urban area for developing drugs abuse, mostly influenced by social and environmental factors. hence, these groups should undergo certain educational programme to prevent not only drug abuse, but also prevent transmission of infectious disease among these groups. introduction: food insecurity is an inequality that is central in the lives of many low-income canadians. our group of university researchers, health professionals, and community developers conducted a study in ottawa with community workers who work with people identified as food insecure. the purpose of the study was to understand the nature of their work, and their perspectives, perceptions and experiences of the causes and consequences of food insecurity. (a parallel study was conducted with food insecure participants). methods: sampling was through local knowledge of organizations involved in the provision of food to community members. written permission for the researchers to contact workers in confidence was obtained from each organization. thirteen in-depth interviews were conducted. the interviews consisted of a number of open-ended questions. the data were collated, and analysed using a grounded approach. results: workers interviewed represented organizations that offered diverse programming and methods of food distribution intended to address the needs of the community. the provision of food was seen as a necessary response to address hunger that arose for the majority from poverty caused by low income, or levels of government income support and safety nets that were insufficient to support food requirements. workers reported that food requirements varied according to different. ethnic backgrounds, ages of recipients and family configurations, and with food preferences, and d'.etary (health) requirements. workers' observations of the effects of insufficient food on adults and children such as depression, low energy and non-participation or social disengagement matched those of food insecure respondents. food insecurity was cited as "another srressor among the mountain of problems." overall, workers presented a picture of a silent, stigmatized, poor population including children, and a lack of advocacy to address the issues. be tha th · ·ty the results suggest that workers and organizations, like the commuruty mem rs t ey msecun • · · · · f ilab'l' f food · t d ·n thei·r ab 'l 'ty to address food insecurity. l m tanons m terms o ava ty o , serve, are restnc e . . funding, and donations appeared to set the para? eters of pr~g:am r.espon~ to commuruty food msecurity. workers were concerned with program des g": and a~m mstranon that m general addr~d hunger on an emergency short-term basis, although food msecunty was long-ter_m for ~any. sustainable solutions that include knowledge translation strategies, and health and social pohcy responses were suggested and will be explored in future research that hopes to build on this pilot. background: socioeconomic deprivation as well as low levels of soc!al s.uppoi:r have .been associated with poor outcomes following cardiac surgery. pre-operative depression m ~anents with coron~ry artery disease awaiting cabg ranges from - % and is an independent predictor of post-operanve mortality. since st. michael's hospital has a large inner city population, this study was designed to determine the both the prevalence of depressive symptomatology (ds) in patients awaiting cabg as well as its relationship with socioeconomic status (ses) and social support. methods: consecutive patients referred for isolated cabg were invited to complete the centre for epidemiological studies depression scale (ces-d) as well as a social support scale and a life stressors inventory. a ces-d score of : represents mild ds and a score of : represents moderate to severe ds. participants also recorded information on functional status, perceived progression of heart failure, demographic and ses variables. all participants with ces-d scores : were considered to have ds. results: of the patients ( %) who returned the survey, ( . %) of participants had a ces-d score : with ( . %) of those having scores suggestive of severe depression. females and those with ongoing medical concerns tended to have more ds (p= . and p= . respectively). age was not related to ds. perceived worsening of symptoms and increased ccs angina class were significantly related to the presence of ds (p= . and p= . respectively) but not the number of diseased heart vessels. satisfaction with personal relationships including having someone to confide in (p= . ), feeling lonely (p= . ) and not having a partner (p= . ) were significantly related to ds. being very upset by a recent breakup in the immediate family was also significantly related to ds (p= . ). having greater than a grade education was the only ses variable related to ds (p= . ). multivariate logistic regression suggested that not being partnered and having low education were the most significant predictors of ds. conclnsion: pre-operative depression is present in at least one quarter of patients referred for cabg. since ds is related to poor outcomes following cabg, single patients with few social supports and low education should be considered at high risk for ds. these findings support the need for the development of supportive interventions in patients at risk in order to decrease post-operative morbidity. this study examines the relationship between childhood sexual abuse, sexual assault during adolescence, and hiv-risk-related behaviours in a sample of homeless youths. over the past decade, there has been increasing research devoted to the impact of childhood sexual abuse. some studies have suggested that the experience of childhood sexual abuse is associated with substance use and abuse, at· risk sexual behaviour and subsequent higher rates of hiv infection (ompad et al., ; cinq-mars et al., ; brown et al., ) . other studies have found that childhood abuse, especially sexual abuse, is c_o~n among stree~ youth (noell et al. ). this study compares sexually abused males and females livtng on the street ~th non-sexually abused street youth, with regards to unsafe sexual behaviours and e~ures to potmnal t:dv sources (e.g., tattooing, body piercing and injection drug use). the hypothe-sis oft~ ~nt study is that the prevalence of hn-risk-related behaviours will be higher among street youth vtctuns of sexual abuse than those who have not been sexually abused. the sample includes youths aged to who met specific criteria's for itinerancy ( male and female, with a mean ~of . y· and a standard deviation of . ). they were recruited through five organisations working ~th~ you~ and were~ of an ongoing cohort study. all youth completed a to minute ques· ~onnaue on their sexual behaviours, use of drugs and alcohol and other hiv risk behaviours. oral spec· unens for hiv testing were. also collected. a total of ( . %) youth reported at least one incident of ~i •~use/assault ( ~ girls ( . % of all the girls) and boys ( . % of all the boys]). preliminary descnpnve analyses pomt to sexually abused/assaulted youth showing the highest prevalence of sexual poster sessions v at-risk behaviours. for example, . % of sexual abuse/assault victims have engaged in prostitution in their lives compared with . % in the non-sexually abused/assaulted group. in addition, . % of sexual abuse/assault victims reported having injected drugs, compared with . % in the non-sexually abused/assaulted group. more statistical analyses will bring other significant factors to light, especially when we analyze separately those victim of childhood sexual abuse as compare to those victim of sexual assault after childhood. elucidating the risk factors for getting involved in hiv-risk-related behaviours is important for the development of comprehensive and appropriate prevention and treatment intervention strategies. introduction: new immigrants and refugees to canada frequently emigrate from regions of the world where intestinal parasitic infections with worms are endemic. of note, some of these parasites area capable of surviving for years to decades within a given host and can have life threatening consequences many years after initial infection. thus, early diagnosis and treatment of intestinal parasitic worms is considered important in high risk immigrant populations, however there remains a lack of consensus regarding the best method of accomplishing this. diagnosing worm infections through stool examinations is costly and has limited sensitivity, while presumptive treatment of all immigrants, although advocated by some, is expensive and results in healthy individuals being unnecessarily treated. herein, we examine the utility of a hematologic marker (i.e. peripheral blood eosinophilia) as a screening instrument to identify parasitic worm infections in new immigrants to toronto. we identified adults, years of age or older, who were screened for intestinal parasitic infections by stool examination as part of a recently developed screening protocol at a downtown toronto community health centre. we examined the prevalence of infections with worms and subsequently evaluated the impact of several demographic factors on the presence of worm infections. we also determined the sensitivity and specificity of peripheral blood eosinophilia (defined as greater than eosinophils per ml) as a marker for intestinal parasitic worm infections. results: overall, % of the immigrants tested had evidence of at least one worm infection on a single stool examination, while % of such individuals bad infections with multiple worms concurrently. age did not appear to be associated with the presence of worms, however % of males had evidence of worm infections compared with % of females (p= . ). immigrants from asia, sub-saharan africa, and central america had the highest burden of overall infection. the sensitivity and specificity of peripheral blood eosinophilia for worm infections was % and % respectively. conclusions: one in five recent immigrants presenting to a community health centre in downtown toronto had evidence of at least one intestinal parasitic worm infection. the highest burden of illness was in men and in those emigrating from less developed regions of the world. peripheral blood eosinophilia is a poor screening test for worm infections however its presence is highly suggestive of the existence of worms in new immigrants. more than a decade ago, the journal of american college health recommended that a national study be conducted to measure the health status of african american college students, 'both health disparities and [their] positive healthful behaviors' (fennell, ) . it was later decided that when exploring the level of health risk behaviors for african american students, gender is an important variable and should be included in the research (fennell, ) . at historically black college and universities (hbcus) college health researchers must tackle gender disparities through highly-effective health promotion and disease prevention programs. the purpose of this review is to examine the literature that addresses the overarching health behaviors (i.e. risky sexual behavior, poor diet, smoking, physical inactivity, etc.) of african american men who attend hbcus. despite the various social, cultural, and academic benefits of african american students who attend hbcus, the number of research studies that adequately address their health and health behaviors is limited. studies indicate that african american men who attend hbcus are actively engaged in poor health behaviors. compared to females at hbcus, african american men are more likely to behave in ways that could result in injuries and the use tobacco, alcohol, and ~ther dru~. the city of toronto has recently proposed to conduct a street count of the homeless. like proposals that have come before, this most recent proposal is controversial among many homeless advocates and service providers because it is perceived as intrusive, likely to undercount the target population, and unnecessary for addressing the problem. advocates of the count view it as necessary to gauge the scope of the problem and advise city leaders about how to most effectively direct resources ro.the various homeless services. this paper first reviews the history of efforts to count homeless populat ns m toronto, describing the motivations and arguments of people on both sides of the issue. second, the paper reviews the methodological complexities of counting homeless populations, describing approaches that use shelter-counts, administrative data and street observations. those interested in counts for toronto and elsewhere can benefit from this review of approaches that have been proposed and carried out in other municipalities. third, the paper proposes a new community-base d strategy that joins the skills of methodologists, local experts, and service providers to ensure a fair and accurate count. the method of systematic social observation avoids some of the problems of early counts by utilizing a repeated identification approach to minimize undercount bias. the method also has the advantage of involving and compensating homeless individuals for assisting with the street count estimates. the estimation approach can be implemented on a rolling basis throughout the year. drug transitions) is a multi-level study aimed at examining the associations between features of the urban environment and mental health, drug use, and risky sexual behaviors. research participants are being recruited in new york city (nyc) neighborhoods. an essential first step in the implementation of this study was to delineate boundaries for each target neighborhood that could then be used to establish sampling frames and as key units of analytic interest. although many neighborhood studies rely on pre-established definitions (e.g. those used for the census or administrative purposes), such definitions do not always reflect contemporary settlement patterns. we felt that street level observations were a neces· sary component of the definition process. methods: the procedures used to delineate neighborhoods were: ( ) development of census block maps of targeted areas; ( ) review of land use maps and census tract data to ensure, prior to going into the field, tha.t particular blocks are residential and likely to have sufficient population for recruitment purposes; and ( ) field vislts and observation in each of the targeted areas. field observations focused on: housing characteristics, including housing type and condition; characteristics of commercial areas, such as likely customer base (e.g. local or no~, socio-economic status and ethnicity of customers); pedestrian volume (including con· gregauons of people m parks and outside stores or residences); obstructions to pedestrian traffic (e.g. ma or thoroughfares, multi-block industry or institutions); and maintenance and use of open spaces. results: in making the final decisions regarding neighborhood boundaries and the inclusion or exclusion of particular. blocks, we considered a broad range of factors including evidence of homogeneity an~ heterogeneity (socmeconomic, ethnic, housing type, environmental) across blocks within and blocks ad acent to a nei.ghborhood, and across the sample neighborhoods; the potential for efficient recruit· ment of appropriate particip.ants (i.e. sufficient local pedestrian traffic); and boundaries used in reporting census data (s? that population data can be used in our analysis). . altho~gh utilization of field observations for neighborhood definitions is relatively time consuming (ap~~ox mately hours for a block area, with more diverse neighborhoods taking even longer), we annc p~t~ that it will substantially improve the quality and consistency of our data gath· ~rmg ~nd analyse~. spec f c e?'amples from neighborhoods defined through this process will be given dur· m~ this presentatmn. we will also discuss the merits and limitations of characterizing neighborhoods usmg street level observations. has been no consideration for how social networks are associated with sse. the objective of this study was to identify personal and social network characteristics associated with being a recipient of sse. in this cross-sectional study, idus who injected in the past months were recruited from syringe exchange programs in montreal, canada, between april and january . information on each participant and on the persons with whom contact had occurred in the past month were elicited using a structured, interviewer-administe red questionnaire. participants provided detailed demographic and drug use information on up to idu members with whom drugs or injecting materials were shared. using logistic regression, personal and network characteristics were examined in relation to receipt of sterile syringes. res.its: of idus, % reported receiving sterile syringes in the past month from another idu. the sample mean age was years (range - ), % male, % caucasian, and % cocaine injectors. in multivariate analyses adjusted for age and gender, recipients of sterile syringes were more likely than non-recipients to share drugs after preparation ( r= . ( . - . )), to require help or to have helped inject another idu (or= . ( . - . )), to have asked someone to get sterile syringes from a syringe exchange program (or= . [ . - . )), to lend syringes (or= . [ . - . ) ) and to use drug preparation water that was previously used by another iou ( r= . ( . - . ) ) during the past months. recipients also had a higher rate of change (p= . ) of idus in their drug injecting network during the past month. with respect to social networks, % ( / ) of idu network members were providers of sterile syringes and were more likely than non-providers to inject everyday (or= . ( . - . )). when stratified by their role as a sexual partner or as someone who provides support (e.g. friend, family member), further risk behaviours were observed in relation to sharing injecting materials with the participant. conclusion: recipients of sterile syringes and their idu network members had several high-risk behaviours for infection with bloodborne diseases. sse may afford an opportunity for the dissemination of other salutary behaviours such as information sharing on safe injecting practices between recipients and distributors. furthermore, drug injecting networks may be an avenue to reach idus who may not otherwise be exposed to preventive measures. there are numerous sources of stigma and labelling of mental and physical illness. first, the sociocultural dimension to stigma and labelling clearly influences patients, families, health care professionals and society's perception and treatment of illness. this creates multiple challenges related to illness identification and recovery, particularly in culturally diverse societies. second, the media is a major source of stigma and stereotyping with regard to a variety of mental and physical illnesses. despite increased public knowledge of many illnesses, studies have shown that stigma has intensified over the years in certain cases. a third element of stigma and labels appears with the use of diagnosis as a solution to human problems with the result that difficult to treat patients are repudiated and social issues are unaddressed. this presentation will serve to outline the development of stigma, various expressions of stigma, and consequences of stigma. it will provide some practical recommendations for the reduction of stigma related to mental and physical illness. purpose: to assess the knowledge, attitude, and practice about immunization for parent of - years old hispanic and african american children in los angeles county (lac). methods: we conducted two cluster surveys in lac. the sample was selected with probability proportionate to estimated size at the first stage and simple random sample of children at the second stage. data were collected through interview. we absuacted vaccine coverage data from immunization record card (irc) at home or from clinic records. the participation was % in hispanics and % in african americans populations. irc was not available at home for % of african american and % of hispanic children. results: all parents perceived their children got all necessary vaccine~. fa~orable attitudes to.w~rd immunization were reported by % of african american and % of h s?amc parents. '.he m~ ority of the parents ( % african american and % hispanic) agreed that vaccines prevent senous d se~ses among children. regarding vaccine safety, significantly more hispanic parents ( %) than african american parents ( %) mentioned that vaccines are safe. introduction: cervical cancer has been shown to be preventable by papanicolau tests in heterosexual women; however, the utility of papanicolau test in lesbians is controversial. cervical cancer is caused by the human papillomavirus (hpv) which is transmitted by sexual _intercourse; howev_er, its' transmission by homosexual intercourse is also controversial. the goal of this study was to review the evidence for papanicolau tests in lesbians. methods: a pub med, ovid ( ovid ( to , and cochrane library search was performed using the mesh headings "homosexuality , female," "vaginal smears," and "papillomavirus, human." in pub med, the clinical queries feature was used with "diagnosis" and "broad, sensitive" filters. a google advanced search of the internet was conducted with the terms "lesbian," "cervical cancer," and "pap rest." the url was limited to ".ca," ".edu," or ".gov." results: the search yielded original articles and reviews, but no cochrane reviews. none of the publications were canadian. website hits were found and selected websites were reviewed. studies showed that lesbians have fewer papanicolau tests than heterosexual women; however, many reported risk factors for cervical cancer, including multiple past or current sexual partners (male and female), early age of first coitus, history of sexually transmitted diseases, and cigarette smoking. hpv has been detected in - % of lesbians and - % of lesbians who have never had sex with men. case studies of abnormal papanicolau tests in lesbians who have never had sex with men have also been reponed. sexual transmission of hpv among lesbians can be explained by several factors: ) - % of lesbians have had sex with men and - % of lesbians continue to have sex with men. ) hpv may be transmitted by sexual behaviours among women, like digital-vaginal sex, digital-anal sex, oral sex, and the use of insertive sex toys. ) hpv transmission requires only skin-to-skin contact. genital hpv has been identified on human fingers. some professional organizations, like the society of obstetricians and gynecologists of canada and the american cancer society, recognize the need for papanicolau tests in lesbians. other organizations, like the canadian cancer society, do not have official policy statements. the current ontario cervical screening program does not specifically address lesbians. conclusion: although the data was limited, most studies recommended that lesbians should receive papanicolau tests. the frequency of these tests was controversial. policy makers and professional organizations should address the needs of this special population and make specific recommendations . monique chaaya, ahia sibai, hiam chemaitelly, and zana el roueiheb . literature concerning the mental and physical effect of work at an old age is contradictory. in addinon, urban environments are physically and socially harsh with reduced potential for income generation and employment and increased potential for depression. the present paper is an attempt to study how do work, or lack of work, link to the experience of depression among older adults in underprivileged lebanese urban communities. the data comes from a cross-sectional survey, where elderly residing in underprivileged communities in beirut, including a palestinian refugee camp, were successfully inter-v ewed through face-to-face interviews. logistic regression was performed to assess the effect of work on depression ad_justing for many other covariates. data showed that . % of people aged years and more were still workmg. there was a highly protective effect of work on depression in elderly males (or= . , % cl= . - . ). the current study is the first of its kind in the arab region and more work shou_ld be _don_e in this area. it is important for the lebanese government to consider elderly rights for social mclus n m terms of employment opportunities. amam nuru-jeter, nancy adler, and burton singer . l~u~on:_ the socioeconomic gradient is perhaps the most persistent and significant finding in social epidem ological research. the insistent nature of the ses effect is evidenced by its significance after acc?untmg for ~umerous confounds. the significance and magnitude of the effect, however, varies by ::•al group. evidence_ o_f the relative effect of race and ses is inconclusive. further, less attention has f ~ ptid to the specific interactions of race and ses than to examinations of which is a better predictor d ~ th. ~sues are further complicated by the explanatory complexity of the various measures of ses anl . owht ey relate to the health of various social groups. understanding the specific nature of these re a ons ips s necessary for guiding he ith d · i · · h a an soc a po mes and programs aimed at improving t e poster sessions v health of our most disadvantaged groups, and therefore population health, overall. this study examines the synergistic effects of ses with both race and gender in predicting group differences in mortality. methods: analyses use data from the national longitudinal mortality survey (n= , ) for the years , , and - ; and were linked to the national death index for deaths occurring through . results were confirmed using data from the national mortality followback survey for people who died in (n= , ) and the national health interview survey (denominator). we used correlation analysis and the standardized mortality ratio to examine ses (education and income), race, and gender as predictors of group differences in changes in mortality. results: for the total population, analyses support the income gradient showing significant declines in mortality ratios from low to high income along the income strata. education shows a significant drop in mortality with completion of high school and completion of college, exhibiting a threshold rather than a gradient effect. compared to whites, blacks receive diminishing health returns for each subsequent level of income and education; with whites closely mirroring the total population in ses thresholds. similarly, compared to men, women do not experience the same health gains at comparable ses levels. for education, black men and women only show significant mortality declines upon completion of high school. the ses gradient operates differently among race and gender subgroups. threshold effects suggest resource gains in life opportunities at particular milestones along the ses gradient. further, ses matters less for blacks and women compared to whites and men suggesting differing implications for health and social policy aimed at reducing disparities. objective: we assessed the impact of diabetes in a large puerto rican community of chicago by measuring the prevalence of diagnosed diabetes and calculating the diabetes mortality rate. methods: we analyzed data from a comprehensive health survey conducted in randomly selected households in community areas. questions on diagnosed diabetes and selected risk factors were asked. in addition, mortality data were analyzed in order to calculate the age-adjusted diabetes mortality rate. when possible, rates were compared to those found in other studies. results: the diabetes prevalence located in this community ( . %: % cl= . %- . %) is one of the highest ever reported for puerto ricans. for instance, it is more than three times higher than the prevalence for the us ( . %) and twice the prevalence for puerto ricans in new york ( . %) and puerto rico ( . %- . %). diagnosed diabetes was found to be significantly associated with obesity (p= . ). the prevalence was particularly high among older people, females, those horn in the us, and those with a family history. the diabetes mortality rate ( . per , population) was more than twice the rate for all of chicago ( . ) and the us ( . ). conclusions: understanding why the diabetes and mortality rates for puerto ricans in this commu· nity are so much higher than those of other communities is imperative. collaboration between researchers, service providers and community members can help address the issues of diabetes education, early screening and diagnosis and effective treatment needed in this community. introduction: sars is a respiratory illness that is spread from person to person through dose contact. this infectious disease outbreak was unusual due to the high rate of infection among health care workers. the aim of the study is to explore the demographic and attitudinal determinants of psychological distress due to sars among health care workers of a toronto hospital. methods: a total of adult participants completed questionnaires co assess psychological distress (impact of event scale -jes) and attitudes to sars. of these, participants completed the questionnaire during the sars i outbreak, and participants completed the questionnaire during the sars ii outbreak. participants also provided information on demographic variables, including occupation and exposure to sars. principal components analysis was used to derive eight attitudinal scales: fear: system, protection, prevention, job stress, stigma, instrumental coping, and psychological copm~. l ear regression analyses were applied to evaluate the associations of the demographic and amtudmal variables, as well as time, with psychological distress. . . regression analyses showed that time and higher scores on fear, ob stress, stigma'. and instrumental coping were associated with a higher total ies score: (r =. ). contrary to expectations, none of the demographic variables was associated with total ies score. conclusion: the presence of psychological distress in health care workers is indicative of intrusive or avoidant responses to thoughts, feelings, and memories associated with the sars outbreak. this study shows that ( ) fear for one's health and the he~lth of.others, ( ) ex~erien~in~ job stress, ( )_tbe per· ception of stigma, ( ) usage of instrumental copmg skills, ~n~ ( ) t m_e s grufi~an~ly c~nmb~te to increased psychological distress in health care workers. potential mterventmns during mfecttous diseaie outbreaks in health care settings should be targeted to minimize the impact of these factors. purpose: the purpose of this study was to expand knowledge regarding feeding practices, know!· edge and nutritional beliefs of mothers currently residing in the dominican republic (dr). the rising incidence of obesity in children is a major national health concern and obesity in first and second-generation immigrant children also continues to rise. we know that parents (particularly mothers) shape children's early diet patterns and that immigrant mothers experience additional challenges related to acculturation and assimilation into a new culture, however there is a paucity of literature concerning the effect of immigrant adaptation to american culture on the nutrition of children. in addition, new immigrant knowledge about the causes of obesity and the resulting health implications for childhood obesity has not been assessed and reported. this qualitative study used focus group methodology to discuss views and practices related to the introduction of food for infants and feeding practices for young children, along with a discussion on knowledge and beliefs related to the causes and health implications of child· hood obesity. ten dominican mothers' of young children (birth to years old) who reside in a small town in the western frontier area of the dr were participants in the focus group. results from this srudy will be compared to results from an identical study that will be conducted in fall with new immi· grant mothers from the dr to the boston area. we will compare feeding practices, beliefs and knowledge about nutrition for young children between these two groups. methods: using participatory principles, a focus group design was used to interview a group of mothers in the dr. the investigator along with a bilingual translator conducted the focus group. the session was tape recorded and is currently in the process of being transcribed and translated. transcribed data will be systematically analyzed themes will be identified. a qualitative data analysis software will be used to organize and code the data according to the specific aims of the study. supporting quotations will be selected to substrate each theme. lmpli~tions for urban health practice: an ultimate goal of this study is to lay a foundation for understanding the process of acculturation on feeding practices of mothers when they immigrate to the us. understanding beliefs, knowledge and feeding practices that mothers use with young children will help m ~he ~evelopment of culturally and linguistically appropriate educational strategies and materials for use m primary prevention of pediatric obesity. in canada more than seventy-five percent of immigrants choose to stay in three major urban centers of toronto, montreal and vancouver. approximately fifty percent of the immigrants eventually set· tie m ~~e greater tor<_>nto area. there is mounting evidence that the increasing immigrant population has a_ sigmfic~nt health disadvantage over canadian-born residents. this health disadvantage manifests particularly m the ma "ority of "mm "gr t h h d be · · h . . . . an s w o a en m canada for longer than ten years. this group as ~n associ~te~ with higher risk of chronic disease such as cardiovascular diseases. this disparity twccb n ma onty of the immigrant population and the canadian-born population is of great importance to ur an health providers d" · i i · b as isproporttonate y arge immigrant population has settled in the ma or ur an centers. generally the health stat f · · · · · · h h been . us most mm grants s dynamic. recent mm grants w o av_e ant •;ffca~ada _for less ~han ~en years are known to have a health advantage known as 'healthy imm • ~ants r::r · ~:s eff~ ~ defined by the observed superior health of both male and female recent immi- immigrant participation in canadian society particularly the labour market. a new explanation of the loss of 'healthy immigrant effect' is given with the help of additional factors. lt appears that the effects of social exclusion from the labour market leading to social inequalities first experienced by recent immigrant has been responsible for the loss of healthy immigrant effect. this loss results in the subsequent health disadvantage observed in the older immigrant population. a study on patients perspectives regarding tuberculosis treatment by s.j.chander, community health cell, bangalore, india. introduction: the national tuberculosis control programme was in place over three decades; still tuberculosis control remains a challenge unmet. every day about people die of tuberculosis in india. tuberculosis affects the poor more and the poor seek help from more than one place due to various reasons. this adversely affects the treatment outcome and the patient's pocket. many tuberculosis patients become non-adherence to treatment due to many reasons. the goal of the study was to understand the patient's perspective regarding tuberculois treatment provided by the bangalore city corporation. (bmc) under the rntcp (revised national tuberculosis control programme) using dots (directly observed treatment, short course) approach. bmc were identified. the information was collected using an in-depth interview technique. they were both male and female aged between - years suffering from pulmonary and extra pulmonary tuberculosis. all patients were from the poor socio economic background. results: most patients who first sought help from private practitioners were not diagnosed and treated correctly. they sought help form them as they were easily accessible and available but they. most patients sought help later than four weeks as they lacked awareness. a few of patients sought help from traditional healers and magicians, as it did not help they turned to allopathic practitioners. the patients interviewed were inadequately informed about various aspect of the disease due to fear of stigma. the patient's family members were generally supportive during the treatment period there was no report of negative attitude of neighbours who were aware of tuberculosis patients instead sympathetic attitude was reported. there exists many myth and misconception associated with marriage and sexual relationship while one suffers from tuberculosis. patients who visited referral hospitals reported that money was demanded for providing services. most patients had to borrow money for treatment. patients want health centres to be clean and be opened on time. they don't like the staff shouting at them to cover their mouth while coughing. conclusion: community education would lead to seek help early and to take preventive measures. adequate patient education would remove all myth and conception and help the patients adhere to treatment. since tb thrives among the poor, poverty eradiation measures need to be given more emphasis. mere treatment approach would not help control tuberculosis. lntrod#ction: the main causative factor in cervical cancer is the presence of oncogenic human papillomavitus (hpv). several factors have been identified in the acquisition of hpv infection and cervical cancer and include early coitarche, large number of lifetime sexual partners, tobacco smoking, poor diet, and concomitant sexually transmitted diseases. it is known that street youth are at much higher risk for these factors and are therefore at higher risk of acquiring hpv infection and cervical cancer. thus, we endeavoured to determine the prevalence of oncogenic hpv infection, and pap test abnormalities, in street youth. ~tbods: this quantitative study uses data collected from a non governmental, not for profit dropin centre for street youth in canada. over one hundred females between the ages of sixteen and twentyfour were enrolled in the study. of these females, all underwent pap testing about those with a previous history of an abnormal pap test, or an abnormal-appearing cervix on clinical examination, underwent hpv-deoxyribonucleic (dna) testing with the digene hybrid capture ii. results: data analysis is underway. the following results will be presented: ) number of positive hpv-dna results, ) pap test results in this group, ) recommended follow-up. . the results of this study will provide information about the prevalence of oncogemc hpv-dna infection and pap test abnormalities in a population of street youth. the practice implic~ tions related to our research include the potential for improved gynecologic care of street youth. in addition, our recommendations on the usefulness of hpv testing in this population will be addressed. methods: a health promotion and disease prevention tool was developed over a period of several years to meet the health needs of recent immigrants and refugees seen at access alliance multicultural community health centre (aamchc), an inner city community health centre in downtown toronto. this instrument was derived from the anecdotal experience of health care providers, a review of medical literature, and con· sultations with experts in migration health. herein we present the individual components of this instrument, aimed at promoting health and preventing disease in new immigrants and refugees to toronto. results: the health promotion and disease prevention tool for immigrants focuses on three primary health related areas: ) globally important infectious diseases including tuberculosis (tb), hiv/aids, syphilis, viral hepatitis, intestinal parasites, and vaccine preventable diseases (vpd), ) cancers caused by infectious diseases or those endemic to developing regions of the world, and ) mental illnesses includiog those developing among survivors of torture. the health needs of new immigrants and refugees are complex, heterogeneous, and ohen reflect conditions found in the immigrant's country of origin. ideally, the management of all new immigrants should be adapted to their experiences prior to migration, however the scale and complexity of this strategy prohibits its general use by healthcare providers in industrialized countries. an immigrant specific disease prevention instrument could help quickly identify and potentially prevent the spread of dangerous infectious diseases, detect cancers at earlier stages of development, and inform health care providers and decision makers about the most effective and efficient strategies to prevent serious illness in new immigrants and refugees. lntrodmction: as poverty continues to grip pakistan, the number of urban street children grows and has now reached alarming proportions, demanding far greater action than presently offered. urbanization, natural catastrophe, drought, disease, war and internal conflict, economic breakdown causing unemployment, and homelessness have forced families and children in search of a "better life," often putting children at risk of abuse and exploitation. objectives: to reduce drug use on the streets in particular injectable drug use and to prevent the transmission of stds/hiv/aids among vulnerable youth. methodology: baseline study and situation assessment of health problems particularly hiv and stds among street children of quetta, pakistan. the program launched a peer education program, including: awareness o_f self and body protection focusing on child sexual abuse, stds/hiv/aids , life skills, gender and sexual rights awareness, preventive health measures, and care at work. it also opened care and counseling center for these working and street children ar.d handed these centers over to local communities. relationships among aids-related knowledge and bt:liefs and sexual behavior of young adults were determined. rea.sons for unsafe sex included: misconception about disease etiology, conflicting cultural values, risk demal, partner pressur~, trust and partner significance, accusation of promiscuity, lack of community endorsement of protecnve measures, and barriers to condom access. in addition socio-economic pressure, physiological issues, poor community participation and anitudes and low ~ducation level limited the effectiveness of existing aids prevention education. according to 'the baseline study the male children are ex~ to ~owledge of safe sex through peers, hakims, and blue films. working children found sexual mfor~anon through older children and their teachers (ustad). recommendation s: it was found that working children are highly vulnerable to stds/hiv/aids, as they lack protective meas":res in sexual abuse and are unaware of safe sexual practices. conclusion: non-fatal overdose was a common occurrence for idu in vancouver, and was associated with several factors considered including crystal methamphetamine use. these findings indicate a need for structural interventions that seek to modify the social and contextual risks for overdose, increased access to treatment programs, and trials of novel interventions such as take-home naloxone programs. background: injection drug users (idus) are at elevated risk for involvement in the criminal justice system due to possession of illicit drugs and participation in drug sales or markets. the criminalization of drug use may produce significant social, economic and health consequences for urban poor drug users. injection-related risks have also been associated with criminal justice involvement or risk of such involvement. previous research has identified racial differences in drug-related arrests and incarceration in the general population. we assess whether criminal justice system involvement differs by race/ethnicity among a community sample of idus. we analyzed data collected from idus (n = , ) who were recruited in san francisco, and interviewed and tested for hiv. criminal justice system involvement was measured by arrest, incarceration, drug felony, and loss/denial of social services associated with the possession of a drug felony. multivariate analyses compared measures of criminal justice involvement and race/ethnicity after adjusting for socio-demographic and drug-use behaviors including drug preference, years of injection drug use, injection frequency, age, housing status, and gender. the six-month prevalence of arrest was highest for whites ( %), compared to african americans ( %) and latinos ( % ), in addition to the mean number of weeks spent in jail in the past months ( . vs. . and . weeks). these differences did not remain statistically significant in multivariate analyses. latinos reported the highest prevalence of a lifetime drug felony conviction ( %) and mean years of lifetime incarceration in prison ( . years), compared to african americans ( %, . years) and whites ( %, . years). being african american was independently associated with having a felony conviction and years of incarceration in prison as compared to whites. the history of involvement in the criminal justice system is widespread in this sample. when looking at racial/ethnic differences over a lifetime including total years of incarceration and drug felony conviction, the involvement of african americans in the criminal justice system is higher as compared to whites. more rigorous examination of these data and others on how criminal justice involvement varies by race, as well as the implications for the health and well-being of idus, is warranted. homelessness is a major social concern that has great im~act on th~se living.in urban commu?ities. metro manila, the capital of the philippines is a highly urbanized ar~ w. t~ the h gh~st concentration of urban poor population-an estimated , families or , , md v duals. this exploratory study v is the first definitive study done in manila that explores the needs and concerns of street dwdlent\omc. less. it aims to establish the demographic profile, lifestyle patterns and needs of the streetdwdlersindit six districts city of manila to establish a database for planning health and other related interventions. based on protocol-guid ed field interviews of street dwellers, the data is useful as a template for ref!!. ence in analyzing urban homelessness in asian developing country contexts. results of the study show that generally, the state of homelessness reflects a feeling of discontent, disenfranchisem ent and pow!!· lessness that contribute to their difficulty in getting out of the streets. the perceived problems andlar dangers in living on the streets are generally associated with their exposure to extreme weather condirioll! and their status of being vagrants making them prone to harassment by the police. the health needs of the street dweller respondents established in this study indicate that the existing health related servias for the homeless poor is ineffective. the street dweller respondents have little or no access to social and health services, if any. some respondents claimed that although they were able to get service from heallh centers or government hospitals, the medicines required for treatment are not usually free and are beyond their means. this group of homeless people needs well-planned interventions to hdp them improve their current situations and support their daily living. the expressed social needs of the sucet dweller respondents were significantly concentrated on the economic aspect, which is, having a perma· nent source of income to afford food, shelter, clothing and education. these reflect the street dweller' s need for personal upliftment and safety. in short, most of their expressed need is a combination of socioeconomic resources that would provide long-term options that are better than the choice of living on the streets. the suggested interventions based on the findings will be discussed. . methods: idu~ aged i and older who injected drugs within the prior month were recruited in usmg rds which relies on referral networks to generate unbiased prevalence estimates. a diverse and mon· vated g~o~p of idu "seeds." were given three uniquely coded coupons and encouraged to refer up to three other ehgibl~ idu~, for which they received $ usd per recruit. all subjects provided informed consent, an anonymous ~t erv ew and a venous blood sample for serologic testing of hiv, hcv and syphilis anti~!· results. a total of idus were recruited in tijuana and in juarez, of whom the maion!)' were .male < .l. % and . %) and median age was . melhotls: using the data from a multi-site survey on health and well being of a random sample of older chinese in seven canadian cities, this paper examined the effects of size of the chinese community and the health status of the aging chinese. the sample (n= , ) consisted of aging chinese aged years and older. physical and mental status of the participants was measured by a chinese version medical outcome study short form sf- . one-way analysis of variance and post-hoc scheffe test were used to test the differences in health status between the participants residing in cities representing three different sizes of the chinese community. regression analysis was also used to examine the contribution of size of the chinese community to physical and mental health status. rmdts: in general, aging chinese who resided in cities with a smaller chinese population were healthier than those who resided in cities with a larger chinese population. the size of the chinese community was significant in predicting both physical and mental health status of the participants. the findings also indicated the potential underlying effects of the variations in country of origin, access barriers, and socio-economic status of the aging chinese in communities with different chinese population size. the study concluded that size of an ethnic community affected the health status of the aging population from the same ethnic community. the intra-group diversity within the aging chinese identified in this study helped to demonstrate the different socio-cultural and structural challenges facing the aging population in different urban settings. urban health and demographic surveillance system, which is implemented by the african population & health research center (aphrc) in two slum settlements of nairobi city. this study focuses on common child illnesses including diarrhea, fever, cough, common cold and malaria, as well as on curative health care service utilization. measures of ses were created using information collected at the household level. other variables of interest included are maternal demographic and cultural factors, and child characteristics. statistical methods appropriate for clustered data were used to identify correlates of child morbidity. preliminary ratdts: morbidity was reported for , ( . %) out of , children accounting for a total of , illness episodes. cough, diarrhoea, runny nose/common cold, abdominal pains, malaria and fever made up the top six forms of morbidity. the only factors that had a significant associ· ation with morbidity were the child's age, ethnicity and type of toilet facility. however, all measures of socioeconomic status (mother's education, socioeconomic status, and mother's work status) had a significant effect on seeking outside care. age of child, severity of illness, type of illness and survival of father and mother were also significantly associated with seeking health care outside home. the results of this study have highlighted the need to address environmental conditions, basic amenities, and livelihood circumstances to improve child health in poor communities. the fact that socioeconomic indicators did not have a significant effect on prevalence of morbidity but were significant for health seeking behavior, indicate that while economic resources may have limited effect in preventing child illnesses when children are living in poor environmental conditions, being enlightened and having greater economic resources would mitigate the impact of the poor environmental conditions and reduce child mortality through better treatment of sick children. inequality in human life chances is about the most visible character of the third world urban space. f.conomic variability and social efficiency have often been fingered to justify such inequalities. within this separation households exist that share similar characteristics and are found to inhabit a given spatial unit of the 'city. the residential geography of cities in the third world is thus characterized by native areas whose core is made up of deteriorated slum property, poor living conditions and a decayed environment; features which personify deprivation in its unimaginable ma~t~de. there are .eviden~es that these conditions are manifested through disturbingly high levels of morbidity and mortality. ban · h h d-and a host of other factors (corrupt n, msens t ve leaders p, poor ur ty on t e one an , . · f · · · th t ) that suggest cracks in the levels and adherence to the prmc p es o socta usnce. ese governance, e c . . . . . ps £factors combine to reinforce the impacts of depnvat n and perpetuate these unpacts. by den· grou o . · "id . . bothh tifying health problems that are caused or driven by either matena _or soc a e~nvanon or , t e paper concludes that deprivation need not be accepted as a way. of hfe a~d a deliberate effon must be made to stem the tide of the on going levels of abject poverty m the third world. to the extent that income related poverty is about the most important of all ramifications of po~erty, efforts n_iu_st include fiscal empowerment of the poor in deprived areas like the inner c~ty. this will ~p~ove ~he willingness of such people to use facilities of care because they are able to effectively demand t, smce m real sense there is no such thing as free medical services. ). there were men with hiv-infection included in the present study (mean age and education of . (sd= . ) and . (sd= . ), respectively). a series of multiple regressions were used to examine the unique contributions of symptom burden (depression, cognitive, pain, fatigue), neuropsychologic al impairment (psychomotor efficiency), demographics (age and education) and hiv disease (cdc- staging) on iirs total score and jirs subscores: ( ) activities of daily living (work, recreation, diet, health, finances); ( ) psychosocial functioning (e.g., self-expression, community involvement); and ( ) intimacy (sex life and relationship with partner). resnlts: total iirs score (r " . ) was associated with aids diagnosis (ii= . , p < . ) and symptoms of pain (ii= - . , p < . ), fatigue (ji = - . , p < . ) and cognitive difficulties (p = . , p < . ). for the three dimensions of the iirs, multiple regression results revealed: ( ) activities of daily living (r = . ) were associated with aids diagnosis (ii = . , p < . ) and symptoms of pain <p =- j , p < . ), fatigue (ji = - . , p < . ) and cognitive difficulties (ji = . , p < . ); ( ) psychosocial functioning (r = . ) was associated with was associated with symptoms of fatigue (ii= - . , p < . ) and cognitive difficulties <ii = . , p < . ); and ( ) intimacy (r = . ) was related to was associated with symptoms of fatigue (ij = - . , p < . ) and cognitive difficulties (ii= . , p < . ). methods: the sif evaluation methodology involves a comprehensive database located at the sif, a randomly selected p~o.spective coh~rt of sif users, and two pre-existing external control cohorts. . . ~ts: in addmon to reporting process data and descriptions of the sif users, we report on data indicating that the establishment of the sif has been independently associated with reductions in public ~':°g ~ (p <?. ), and syringe sharing (aor = . [ %ci: . _ . ); p = . ) and other unsafe m ecnon pract _ces_ (p ~ . ), and increased uptake of detox services (log-rank p = . ). as well, we report on da~ md cat ng that the sif has not prompted adverse changes in community drug use patterns. the vancouver sif has been well accepted by the target population, and while adve~ events s~c~ as overdoses have occurred, these events have been successfully managed. externally compiled data indicate that the sif has been associated with substantial declines in public disorder !'oster sessions v associated with injection drug use, syringe sharing, and increased uptake of detox services. as well, the establishment of the sif has not exacerbated community drug use patterns. ongoing evaluation activities wiu involve assessing the impact of the sif on a variety of outcomes, including infectious disease transmission, fatal overdose, and utilization of health and social services. city, brazil, - maria cristina almeida, waleska caiaffa, renato assum;iio, and fernando proietti dengue cases were described according to time, space, intensity, age, gender, onset of symptoms, residence address and census tract. spatial distribution of two groups (children and women over years old and men aged - ) were compared, under assumption that they have distinct behaviors regarding their displacement around the city. analysis included local moran index, ripley\\'s k function and recurrence of census areas over time. about , cases were identified in seven epidemic waves. concentration of cases in small areas, followed by a spread either in space or time suggested endemic patterns. regarding age-gender groups, distinct patterns suggested that residence might not be a good proxy in determining the local of infection for men aged - . dengue is shifting to endemic pattern in this city and transmission may not be sole related to home environment, suggesting that additional spatial information must be couected aiming efficient control measures. murukan kandamuthan and subodh kandamuthan lnl uduction: illness or disablement of a child may affect the economic functioning of a family as it alters the employment pattern and earnings of parents this paper tries to assess the health status and the quality of life of disabled children, and how generally, severe disablement in a child affected their fami-lies\' finances, and to quantify any such effects the problems faced by children in their home and to provide information relevant to the formation of criteria for new or increased cash support. methods: a case-control study was done in the thiruvananthapuram district, capital city of kerala by selecting a random sample of families with severely disabled children below years and a random sample of normal children matched for age and occupation of the parents. comparative and subjective data were collected. money spent on children\'s medical care, loss of earnings of the parents, and other economic burden to the family due to the disability of the child in the family. a discriminant analysis along with univariate analysis was done to assess the factors that mostly differentiate the disabled and normal children. the mean expenditure of the families with a disabled child was rs. /-per month, which is significantly higher than the corresponding expenditure of rs. /-per month of families with normal child, (t= . , p <. ). of the disabled children, % were not getting any social security payments and % had no special concessions for medical and other educational purposes. the analysis of income and expenditure pattern indicated that financial impact of disablement in a child on the family is significant. the discriminant model results revealed that medical expenditure was a significant variable that differentiated the disabled and normal child. the study found that the health status and quality of life of the disabled children were far from satisfactory. this in fact affected the economic status of the disabled children. in addition to reduced earnings, there are extra costs for disabled children for travel, domestic help, medical care, and health care expenditures (hospital care, physician services, dentistry, drugs and others) for disabled individuals. a strong case can be made for their long-term care by improving the financial support to such families possibly through the introduction of an allowance specially to compensate for the earnings lost by parents due to the disability of their children. widows in india are considered disadvantage group of population. because they are characterized by pangs of separation from spouse, and consequently they go through mental agony, social ~s?lation, and economic dislocation. in addition to these, poverty, landlessness, homelessness, malnutr non etc. endure serious deterioration of their health. according to census , there are million women are widowed and one fourth live in urban areas. there is a noticeable increase of urban widows from the previous census (almost half). the paper examines the type of disability and chronic ailment borne among elderly widows ( years and above). fifty second round of national sample survey aske~ the individuals three sets of questions regarding their health: their status of health, whether they are physically poster sessions v immobile, and whether or not they have had any specific chronic illnesses. although health infrastruc- · ble ·n urban setting in india as compared to rural counterpart, prevalence of tures are arge y ava a . . . . . h · · · h h"gher "n urban areas analysis shows omt problems m old age qmte common c romc ness is muc • . . and nearly percent elderly widows are suffering from this ail'. ent in urban areas. one-fifth of widows are suffering from high/low bp. heart disease, diabetes and urinary problems are much ~ore pre~alent in urban areas though disabilities is comparatively lower in urban areas. however, the d~fference is not statistically significant. disability with respect to vision is more pronounced and one third_ of the total respondents have problems regarding eyesight. one fifths ofdderly widows are _ha.rd of hearing. though disability increases with age, similar trend is not observed with respect to chr~mc illness. the percepnon of self-health among elderly becomes poorer as their age increases. the perceived health status need not be always corrected to objective indicators of health. it is noted that around per~en~ of those perceived their health as "excellenr" or "very good" are found to be suffering from chrome disease of omts and percent have visual disability. to conclude an elderly widow living in urban areas have similar health problems as she jives in rural areas. this can be easily explained, as they were not made aware to seek treatment from health facility. in addition, the study shows that the economic conditions are deterrent factors for their illness. it is essential that intervention should be taken up improving their economic conditions so that wellbeing of this most vulnerable group of the society can be taken care of. heart failure is a disease that affects nearly million people world wide. the united states alone accounts for one third of this population. blacks are stricken with heart failure twice as often as whites. men are more likely to develop chf than women, however since the majority of the chf population are seniors, there are actually more women than men. congestive heart failure (chf) has become a pandemic. as the baby boomer generation ages, the number of chf cases will rise dramatically. (young, j. & mills, r., ). after the age of , each proceeding decade doubles the incidence level of chf. the average person has a in chance of developing heart failure within their lifespan according to the framingham study (nih.gov). individuals aging or older compose over half of the entire documented heart failure population. in this age group, chf is the leading cause of hospitalization. many patients are continuously readmitted. it is estimated that the chf population will increase by one million within the next years. mortality was at % for a two year period and % for five years (young, j. & mills, r., ). data from: aha as technology evolves, the understanding of the nature of heart failure has become clearer. in the beginning of the th century heart failure was diagnosed as a condition that presented with edema (swelling) in the extremities caused by water retention. treatment in the beginning of the past cenrury was limited to abdominal drainage and diuretics. the discovery of the heart's insufficient pumping ability in heart failure patients lead to new surgeries and devices such as heart transplants and ventricular assist devices (bridge until transplant is available). ventricular hypertrophy often occurs before the development of heart failure. hypertrophy is the term given for cardiac remodeling. cardiac remodeling also includes chamber dilation (young, j. & mills, r., ) . chf financial burden the us healthcare financing administration has ranked chf as the highest cost illness in the diagnose-related area. direct costs related to chf in the us for were nearly $ billion. these costs included hospital admissions, physician fees, home health aids and medications. indirect costs were over $ billion in . loss of jobs or death due to chf was the criteria for this category (young, j. & mills, r., ). . introduction: the injection drug user quality of life scale (iduqol) is a relatively new scale ~es gned to capture the unique and individual circumstances that determine quality of life among injection drug users (idus). the life areas comprising the instrument were based on the research literature an~ ~ocus group discussions with idus. the purpose of the present study was to evaluate the content validity of t.h~ iduqol using judgmental methods based on subject matter experts' (smes) ratings. content vah~ ty refers to the de~ee to which elements of an assessment tool are representative of the construct of interest and appropnate for a given population. methods: data were obtained from six smes, from the field of idu research and practice, who ~ere. asked t.o evaluate various aspects of the iduqol, including the title of the instrument, administraon instruchons, clarity of the names and descriptions of each life area, response format, scoring instruc-no~s and examples, record form and whether each life area should be included in the instrument. sme ratings were made using either or point scales. sm es were also given the opportunity to comment on poster sessions v each section and to suggest whether important life areas had been overlooked, were redundant, not relevant, or in need of revision. (cvi) and the ~v.erage ~eviation index (ad) were used to evaluate smes' agreement on ratings of the content vahd ty vanables. both measures provided support for the content validity of various aspects of the iduqol, although results from the stricter ad index noted some areas of disagreement, including the description of particular life areas (e.g., being useful, drugs, sex), the inclusion of some life areas (e.g., drug treatment, education, independence and free choice), and the ease of the scoring instructions. the findings from this study provide (a) content validity evidence to support the use of the iduqol as well as (b) recommendations to suengthen both the instrument (e.g., improved descriptions for some items) and the accompanying administration and scoring manual (e.g., an easier scoring template). changes made to the instrument and its manual make the iduqol even easier for researchers, practitioners, and program evaluators to use as a way of assessing, and tracking changes over time or as a result of interventions in, quality of life in injection drug users. introduction: strict adherence to prescribed regimens is required to derive maximal benefit from highly active antireuoviral therapy (haart) in persons living with hiv/aids (phas). adherence is a key determinant of the degree and durability of viral suppression. adherence is also essential in reducing the spread of hiv and ensuring that today's treatments remain effective for as long as possible. the objective of this study is to conduct a systematic review of the research literature on the effectiveness of education and patient support strategies for improving adherence to haart. methods: a systematic search of the core databases was performed from january until may . randomized controlled trials examining the effectiveness of education and patient support interventions to improve the adherence to haart were considered for inclusion. only those studies that measured adherence at a minimum of six weeks were included. study selection, quality assessments, and data abstraction were performed independently by two reviewers. results: study heterogeneity with respect to differing populations, interventions, outcomes, and length of follow-up did not allow for meta-analysis. we included studies involving , ph as. sample sizes ranged from to . study duration ranged from a single session to a variable number of sessions delivered over one year. many of the interventions involved the provision of an educational component to improve adherence and often addressed strategies to overcome barriers to adherence and the development of problem-solving skills. they ranged from simple interventions (e.g., the provision of reminder devices) to complex interventions (e.g., cognitive-behavioural therapy delivered by licensed psychologists). eleven of the studies demonstrated a statistically significant advantage associated with the described adherence intervention. the advantage associated with adherence outcomes does not seem to translate into the more clinically relevant outcome of viral suppression. only out of studies that reported virological or immunological results found a significant effect associated with the intervention. the studies had several methodological shortcomings. conclusions: there is a need for standardization and methodological rigour in the conduct of adherence trials. some interventions may have a significant impact on improving adherence. further research is required before any specific adherence improving strategy can confidently be incorporated into standard clinical practice. focus groups were used to collect data from a purposive sample of treatmentexperienced participants. focus group data were analyzed using a grou~ded t~eory appr~ach. i:ne themes identified from the interviews were used to identify the effects of ant rerrov rals on quality of hfe. the content of the mos-hiv was appraised against the themes identified from our analysis. participants also completed the mos-hiv survey and were asked whether the survey covered all important aspects of quality of life on antiretroviral medications. results: five key informant interviews and five focus groups with participants were used to identify effects on quality of life that are not directly ~aptu~ed by_ the mos-hiv health survey. our~~ showed that our participants described quality of hfe as mvol~mg_ a set of ~rsonal trad~ffs ~stay alive. in most cases, worsened quality of life was traded-off for gams ~ longevlty from ~~canon use. these eff~'ts or tradeoffs included: ( ) downstream consequences of side effects and toxlanes; ( ) loss of lrufe. pende~t decision-making privileges, ( ) having to choose drugs over ~areer; (~)burden of medication-taking responsibilities; and ( ) living life under a pretense and havmg to hide-the net effect of the tradeoffs, or "prices" to pay led to what was described as "longevity with hn without hope and future~. conclusion: our study highlights five major themes summarizing the impact of haart on quality on life, and suggests that currently used scales for measuring quality of life do not a~atd~ cap~e these findings and the associated consequences. the conceptual framework for measuring quality of bfe in hiv should be reconsidered in order to better capture the important effects of the medications on quality of life. this may involve widening the boundaries of the definition of health-related quality oflife to include aspects such as finances, employment, and housing. we should further consider the development of a haart adverse effect specific instrument, using a broad definition of adverse effect in order to capture all types of adverse impacts of hiv treatments on quality of life. introduction: measles (rubeola) is the most contagious vaccine preventable disease of humans. while cases of measles are uncommon in canada today, the disease continues to be a leading cause of morbidity and death in the developing world. as a result of human migration, measles cases still occur in canada, primari~ among immigrants, returning travelers, and other susceptible groups. canada's national advisory council on immunizations (naci) recommends that immigrants without records of measles immunization be considered for vac:cination since these individuals may not have been appropriately vaccinated in their native country. on rhe other hand, natural immunity to measles in immigrants is likely to be high given the high incidence of disease in developing parts of rhe world. thus it remains unclear if the most efficient strategy to achieve high levels of measles immunity in immigrants should entail initial serologic screening followed by vaccination of susceptible individuals or preemptive vaccination of all persons lacking immunization records. understanding the epidemiology of measles immunity in immigrant populations could help guide such decisions. . methods: we identified adults, years of age or older, who were screened for serologtc immunity to measles as part of a recently developed screening protocol at a downtown toronto community health centre. we subsequently determined if these individuals had any immunization records from their native country or from within canada. we then examined the relationship between several demographic factors and immunity to measles. results: % of immigrants had no prior immunization records. overall, % of the immigrants rested for immunity to measles were found to be immune; % of those under the age of , % of those between and years of age, % of those between and years of age, and % of those years of age or older. gender, education status, household income, and immigration status were nor ~ssoc ated wirh immunity to measles. immunity to measles was lowest among immigrants from eastern europe ( ~%), whil~ immigrants from other regions of the globe had greater than % immunity. c~lusrons: immigrants and refugees appear to have reasonably high levels of immunity to mea· sics, possibly related to natural infection wirh the measles virus. immigrants from eastern europe appear to have slightly. lower l~vel~ of immunity to the measles virus. universal screening for immunity to meales or preemptive vac:cmauon may both be inefficient public health strategies, however further research is needed to corroborate these findings. nancy r~ss, stephane tremblay, saeeda khan, daniel crouse, mark tremblay, and jean-marie berrhelor o~ve: the speed of the rise in obesity in places like canada suggests that rather than a shift in the gcncnc_ com~sirion of the population, the root of the obesity pandemic is an environment that suprrs ~besity. this paper examines the influence of neighbourhood and metropolitan characteristics. bour~lts:. while accounting. for individual socio-demographics and behaviours, residents of neighs with a large proportmn of poorly educated individuals had higher bmis than those living in poster sessions v neighbourhoods with more highly educated individuals (p <. ). residing in a neighbourhood with a high proportion of recent immigrants was associated with lower bmi for men (p<. ), but not women. neighbourhood dwelling density, a proxy for walkability, was not associated with bm! for either sex. metropolitan sprawl was associated with higher male bmi (p=. ) but the effect was negligible for women (p=. ). bmi was significantly lower for women (p<. ) living in a city in the province of quebec, even after accounting for the influence of individual and neighbourhood covariates. conclusions: bm! was strongly patterned by individual-level social position in urban canada. the incremental influence on bmi of neighbourhood related to the neighbourhood's social conditions and not to their physical form. metropolitan sprawl was associated with higher bm! for men, a group with longer car-dependent commutes than women. the findings suggest that both individuals and their environments (both social and physical) influence the distribution of bmi in urban populations. introduction: urban environments have been linked to a range of human health issues. in singapore, prevalence of end stage renal disease (esrd) is predicted to rise ( in to in , kidney international, vol. , . the clinical and economic burden of esrd has promoted development of strategies aimed at preventing the development and progression of chronic kidney disease. these include population based screening programs such as the national kidney foundation, sin-gapore\'s (nkfs) "partnership for prevention."the program, aims to reduce incidence of esrd through comprehensive intervention and screening for early detection of urinary abnormalities, blood pressure (bp), and random blood glucose (rbg). objective of this study is to examine gender, race and age wise prevalence of elevated bp, rbg and proteinuria. methodology: this current analysis includes , subjects, age to years, who underwent screening during september and december . participants were asked to give demographic information and the history of diseases. tests were given to get clinical information such as proteinuria, blood glucose, sbp, and dbp. blood pressure abnormalities were defined according to ]nc vi criteria. proteinuria was defined as the presence of plus or greater protein (equivalent to> mg/di) on dipstick analysis. results: there were , ( . %) males. racial distribution was chinese ( . % ), malay ( . % ), indians ( . %) and others ( . % ).among participants, who were apparently "healthy" (asymptomatic and without history of dm, ht, or kd), gender and race wise % prevalence of elevated (bp> / ), rbg (> mg/di) and positive urine dipstick for protein was as follows male: ( . ; . ; . ) female:( . ; . ; . ) chinese:( . ; . ; ) malay: ( . ; . ; . ) indian:( . ; . ; . ) others: ( . ; . ; . ) total:(l . , . , . ). percentage of participants with more than one abnormality were as follows. those with bp> / mmhg, % also had rbg> mg/dl and . % had proteinuria> i. those with rbg> mgldl, % also had proteinuria> and % had bp> / mmhg. those with proteinuria> , % also had rbg> mg/dl, and % had bp> / mmhg. conclusion: we conclude that sub clinical abnormalities in urinalysis, bp and rbg readings are prevalent across all genders and racial groups in the adult population. the overlap of abnormalities, point towards the high risk for esrd as well as cardiovascular disease. this indicates the urgent need for population based programs aimed at creating awareness, and initiatives to control and retard progression of disease. introduction: various theories have been proposed that link differential psychological vulnerability to health outcomes, including developmental theories about attachment, separation, and the formation of psychopathology. research in the area of psychosomatic medicine suggests an association between attachment style and physical illness, with stress as a mediator. there are two main hypotheses explored in the present study: ( t) that individuals living with hiv who were upsychologically vulne~able" at study entry would be more likely to experience symptoms of depression, anxiety and phys ca! illness over. the course of the -month study period; and ( ) life stressors and social support would mediate the relat nship between psychological vulnerability and the psychological ~nd physical outcomes. . (rsles), state-trait anxiety inventory (stai), beck depr~ssi~n lnvento~ (bdi), and~ _ -item pbys~i symptoms inventory. we characterized participants as havmg psychological vulnerability and low resilience" as scoring above on the raas (insecure attachment) or above on the das (negative expectations about oneself). . . . . . " . . ,, . results: at baseline, % of parnc pants were classified as havmg low resilience. focusmg on anxiety, the average cumulative stai score of the low-resilience group was significandy hi~e~ than that of the high-resilience group ( . sd= . versus . sd= . ; f(l, )= . , p <. ). similar results were obtained for bdi and physical symptoms (f( , )= . , p<. and f( , )= . , p<. , respec· tively). after controlling for resilience, the effects of variance in life stres".°rs averaged over time wa~ a_sig· nificant predictor of depressive and physical symptoms, but not of anxiety. ho~e_ver, these assooan~s became non-significant when four participants with high values were removed. s id larly, after controlling for resilience, the effects of variance in social support averaged over time became insignificant. conclusion: not only did "low resilience" predict poor psychological and physical outcomes, it was also predictive of life events and social support; that is, individuals who were low in resilience were more likely to experience more life events and poorer social support than individuals who were resilient. for individuals with vulnerability to physical, psychological, and social outcomes, there is need to develop and test interventions to improve health outcomes in this group. rajat kapoor, ruby gupta, and jugal kishore introduction: young people in india represent almost one-fourth of the total population. they face significant risks related to sexual and reproductive health. many lack the information and skills neces· sary to make informed sexual and reproductive health choices. objective: to study the level of awareness about contraceptives among youth residing in urban and rural areas of delhi. method: a sample of youths was selected from barwala (rural; n= ) and balmiki basti (urban slums; n= ) the field practice areas of the department of community medicine, maulana azad medical college, in delhi. a pre-tested questionnaire was used to collect the information. when/(calen· dar time), by , fisher exact and t were appliedxwhom (authors?). statistical tests such as as appropriate. result: nearly out of ( . %) youth had heard of at least one type of contraceptive and majority ( . %) had heard about condoms. however, awareness regarding usage of contraceptives was as low as . % for terminal methods to . % for condom. condom was the best technique before and after marriage and also after childbirth. the difference in rural and urban groups was statistically signif· icant (p=. , give confidence interval too, if you provide the exact p value). youth knew that contra· ceptives were easily available ( %), mainly at dispensary ( . %) and chemist shops ( . %). only . % knew about emergency contraception. only advantage of contraceptives cited was population con· trol ( . %); however, . % believed that they could also control hiv transmission. awareness of side effects was poor among both the groups but the differences were statistically significant for pills (p= . ). media was the main source of information ( %). majority of youth was willing to discuss a~ut contraceptive with their spouse ( . %), but not with others. . % youth believed that people in their age group use contraceptives. % of youth accepted that they had used contraceptives at least once. % felt children in family is appropriate, but only . % believed in year spacing. . conclusion: awareness about contraceptives is vital for youth to protect their sexual and reproduc· tive health .. knowledge about terminal methods, emergency contraception, and side effects of various contraceptives need to be strengthened in mass media and contraceptive awareness campaigns. mdbot:ls: elderly aged + were interviewed in poor communities in beirut the capital of f:ebanon, ~e of which is a palestinia~. refugee camp. depression was assessed using the i -item geriat· nc depressi~n score (~l?s- ). specific q~estions relating to the aspects of religiosity were asked as well as questions perta rung to demographic, psychosocial and health-related variables. results: depression was prevalent in % of the interviewed elderly with the highest proportion being in the palestinian refugee camp ( %). mosque attendance significantly reduced the odds of being depressed only for the palestinian respondents. depression was further associated, in particular communities, with low satisfaction with income, functional disability, and illness during last year. condiuion: religious practice, which was only related to depression among the refugee population, is discussed as more of an indicator of social cohesion, solidarity than an aspect of religiosity. furthermore, it has been suggested that minority groups rely on religious stratagems to cope with their pain more than other groups. implications of findings are discussed with particular relevance to the populations studied. nearly thirty percent of india's population lives in urban areas. the outcome of urbanization has resulted in rapid growth of urban slums. in a mega-city chennai, the slum populations ( . percent) face greater health hazards due to overcrowding, poor sanitation, lack of access to safe drinking water and environmental pollution. amongst the slum population the health of women and children are most neglected, resulting in burden of both communicable and non-communicable diseases. the focus of the paper is to present the epidemiology profile of children (below years) in slums of chennai, their health status, hygiene and nutritional factors, the social response to health, the trends in child health and urbanization over a decade, the health accessibility factors, the role of gender in health care and assessment impact of health education to children. the available data prove that child health in slums is worse than rural areas. though the slum population is decreasing there is a need to explore the program intervention and carry out surveys for collecting data on some specific health implications of the slum children. objective: during the summer of there was a heat wave in central europe, producing an excess number of deaths in many countries including spain. the city of barcelona was one of the places in spain where temperatures often surpassed the excess heat threshold related with an increase in mortality. the objective of the study was to determine whether the excess of mortality which occurred in barcelona was dependent on age, gender or educational level, important but often neglected dimensions of heat wave-related studies. methods: barcelona, the second largest city in spain ( , , inhabitants in ) , is located on the north eastern coast. we included all deaths of residents of barcelona older than years that occurred in the city during the months of june, july and august of and also during the same months during the preceding years. all the analyses were performed for each sex separately. the daily number of deaths in the year was compared with the mean daily number of deaths for the period - for each educational level. poisson regression models were fitted to obtain the rr of death in with respect to the period - for each educational level and age group. results: the excess of mortality during that summer was more important for women than for men and among older ages. although the increase was observed in all educational groups, in some age-groups the increase was larger for people with less than primary education. for example, for women in the group aged - , the rr of dying for compared to - for women with no education was . ( %ci: . - - ) and for women with primary education or higher was . ( %ci: . - . ). when we consider the number of excess deaths, for total mortality (>= years) the excess numbers were higher for those with no education ( . for women and . for men) and those with less than primary education ( . for women and - for men) than those with more than primary edm:ation ( . for women and - . for men). conclusion: age, gender and educational level were important in the barcelona heat wave. it is necessary to implement response plans to reduce heat morbidity and mortality. policies should he addressed to all population but also focusing particularly to the oldest population of low educational level. introduction: recently there has been much public discourse on homelessness and its imp~ct on health. measures have intensified to get people off the street into permanent housing. for maximum v poster sessions success it is important to first determine the needs of those to be housed. their views on housing and support requirements have to be considered, as th~y ar~ the ones affected. as few res.earch studies mclude the perspectives of homeless people themselves, httle is known on ho~ they e~penence the mpacrs on their health and what kinds of supports they believe they need to obtain housing and stay housed. the purpose of this study was to add the perspectives of homeless people to the discourse, based in the assumption that they are the experts on their own situations and needs. housing is seen as a major deter· minant of health. the research questions were: what are the effects of homelessness on health? what kind of supports are needed for homeless people to get off the street? both questions sought the views of homeless individuals on these issues. methods: this study is qualitative, descriptive, exploratory. semi-structured interviews were conducted with homeless persons on street corners, in parks and drop-ins. subsequently a thematic analysis was carried out on the data. results: the findings show that individuals' experiences of homelessness deeply affect their health. apart from physical impacts all talked about how their emotional health and self-esteem are affected. the system itself, rather than being useful, was often perceived as disabling and dehumanizing, resulting in hopelessness and resignation to life on the street. neither welfare nor minimum wage jobs are sufficient to live and pay rent. educational upgrading and job training, rather than enforced idleness, are desired by most initially. in general, the longer persons were homeless, the more they fell into patterned cycles of shelter /street life, temporary employment /unemployment, sometimes addictions and often unsuccessful housing episodes. conclusions: participants believe that resources should be put into training and education for acquisition of job skills and confidence to avoid homelessness or minimize its duration. to afford housing low-income people and welfare recipients need subsidies. early interventions, 'housing first', more humane and efficient processes for negotiating the welfare system, respectful treatment by service providers and some extra financial support in crisis initially, were suggested as helpful for avoiding homelessness altogether or helping most homeless people to leave the street. this study is a national homelessness initiative funded analysis examining the experiences and perceptions of street youth vis-a-vis their health/wellness status. through in-depth interviews with street youth in halifax, montreal, toronto, calgary, ottawa and vancouver, this paper explores healthy and not-so healthy practices of young people living on the street. qualitative interviews with health/ social service providers complement the analysis. more specifically, the investigation uncovers how street youth understand health and wellness; how they define good and bad health; and their experiences in accessing diverse health services. findings suggest that living on the street impacts physical, emotional and spiritual well·being, leading to cycles of despair, anger and helplessness. the majority of street youth services act as "brokers" for young people who desire health care services yet refuse to approach formal heal~h care organizational structures. as such, this study also provides case examples of promising youth services across canada who are emerging as critical spaces for street youth to heal from the ravages of ~treet cultur~. as young people increasingly make up a substantial proportion of the homeless population in canada, it becomes urgent to explore the multiple ways in which we can support them to regain a sense of wellbeing and "citizenship." p - (c) health and livelihood implications of marginalization of slum dwellers in provision of water and sanitation services in nairobi city elizabeth kimani, eliya zulu, and chi-chi undie . ~ntrodfldion: un-habitat estimates that % of urban residents in kenya live in slums; yet due to their illegal status, they are not provided with basic services such as water sanitation and health care. ~nseque~tly, the services are provided by vendors who typically provide' poor services at exorbitant prices .. this paper investigates how the inequality in provision of basic services affects health and livelihood circumstances of the poor residents of nairobi slums . . methods: this study uses qualitative and quantitative data collected through the ongoing longitudmal .health and demographic study conducted by the african population and health research center m slum communities in n ·rob" w d · · · · ai . e use escnpnve analytical and qualitative techmques to assess h~w concerns relating to water supply and environmental sanitation services rank among the c~mmumty's general and health needs/concerns, and how this context affect their health and livelihood circumstances. results: water ( %) and sanitation ( %) were the most commonly reported health needs and also key among general needs (after unemployment) among slum dwellers. water and sanitation services are mainly provided by exploitative vendors who operate without any regulatory mechanism and charge exorbitantly for their poor services. for instance slum residents pay about times more for water than non-slum households. water supply is irregular and residents often go for a week without water; prices are hiked and hygiene is compromised during such shortages. most houses do not have toilets and residents have to use commercial toilets or adopt unorthodox means such as disposing of their excreta in the nearby bushes or plastic bags that they throw in the open. as a direct result of the poor environmental conditions and inaccessible health services, slum residents are not only sicker, they are also less likely to utilise health services and consequently, more likely to die than non-slum residents. for instance, the prevalence of diarrhoea among children in the slums was % compared to % in nairobi as a whole and % in rural areas, while under-five mortality rates were / , / and / respectively. the results demonstrate the need for change in governments' policies that deprive the rapidly expanding urban poor population of basic services and regulatory mechanisms that would protect them from exploitation. the poor environmental sanitation and lack of basic services compound slum residents' poverty since they pay much more for the relatively poor services than their non-slum counterparts, and also increase their vulnerability to infectious diseases and mortality. since iepas've been working in harm reduction becoming the pioneer in latin america that brought this methodology for brazil. nowadays the main goal is to expand this strategy in the region and strive to change the drug policy in brazil. in this way harm reduction: health and citizenship program work in two areas to promote the citizenship of !du and for people living with hiv/aids offering law assistance for this population and outreach work for needle exchange to reduce damages and dissemination of hiv/aids/hepatit is. the methodology used in outreach work is peer education, needle exchange, condoms and folders distribution to reduce damages and the dissemination of diseases like hiv/aids/hepatitis besides counseling to search for basic health and rights are activities in this program. law attendance for the target population at iepas headquarters every week in order to provide law assistance that includes only supply people with correct law information or file a lawsuit. presentations in harm reduction and drug policy to expand these subjects for police chiefs and governmental in the last year attended !du and nidu reached and . needles and syringes exchanged. in law assistance ( people living with aids, drug users, inject drug users, were not in profile) people attended. lawsuits filed lawsuits in current activity. broadcasting of the harm reduction strategies by the press helps to move the public opinion, gather supporters and diminish controversies regarding such actions. a majority number of police officer doesn't know the existence of this policy. it's still polemic discuss this subject in this part of population. women remain one of the most under seviced segments of the nigerian populationand a focus on their health and other needs is of special importance.the singular focus of the nigerian family welfare program is mostly on demographic targets by seeking to increase contraceptive prevalence.this has meant the neglect of many areas of of women's reproductive health. reproductive health is affected by a variety of socio-cultural and biological factors on on e hand and the quality of the service delivery system and its responsiveness on the other.a woman's based approach is one which responds to the needs of the adult woman and adolescent girls in a culturally sensitive manner.women's unequal access to resources including health care is well known in nigeria in which stark gender disparities are a reality .maternal health activities are unbalanced,focusi ng on immunisation and provision of iron and folic acid,rather than on sustained care of women or on the detection and referral of high risk cases. a cross-sectional study of a municipal government -owned hospitalfrom each of the geo-political regions in igeria was carried out (atotal of ce~ters) .. as _part ~f t~e re.search, the h~spital records were uesd as a background in addition to a -week mtens ve mvesuganon m the obstemc and gynecology departments. . . . : little is known for example of the extent of gynecological morbtdtty among women; the little known suggest that teh majority suffer from one or more reproductive tr~ct infect~ons. although abortion is widespread, it continues to be performed under ilegal and unsafe condmons. with the growing v poster sessions hiv pandemic, while high riskgroups such ascomn;iercial sex workers and their clients have been studied, little has been accomplished in the large populat ns, and particularly among women, regardmgstd an hiv education. . . conclusions: programs of various governmentalor non-governmental agen,c es to mvolve strategies to broaden the narrow focus of services, and more importan~, to put wo~en s reproducnve health services and information needs in the forefront are urgently required. there is a n~d to reonent commuication and education activities to incorprate a wider interpretation of reproducnve health, to focus on the varying information needs of women, men, and youth and to the media most suitable to convey information to these diverse groups on reproductive health. introduction: it is estimated that there are - youths living on the streets, on their own with the assistance of social services or in poverty with a parent in ottawa. this population is under-serviced in many areas including health care. many of these adolescents are uncomfortable or unable to access the health care system through conventional methods and have been treated in walk-in clinics and emergency rooms without ongoing follow up. in march , the ontario government provided the ct lamont institute with a grant to open an interdisciplinary and teaching medical/dental clinic for street youth in a drop-in center in downtown ottawa. bringing community organizations together to provide primary medical care and dental hygiene to the streetyouths of ottawa ages - , it is staffed by a family physician, family medicine residents, a nurse practitioner, public health nurses, a dental hygienist, dental hygiene students and a chiropodist who link to social services already provided at the centre including housing, life skills programs and counselling. project objectives: . to improve the health of high risk youth by providing accessible, coordinated, comprehensive health and dental care to vulnerable adolescents. . to model and teach interdisciplinary adolescent care to undergraduate medical students, family medicine residents and dental hygiene students. methods: non-randomized, mixed method design involving a process and impact evaluation. data collection-qualitative:a) semi-structured interviews b) focus groups with youth quantitative:a) electronic medical records for months b) records (budget, photos, project information). results: in progress-results from first months available in august . early results suggest that locating the clinic in a safe and familiar environment is a key factor in attracting the over youths the clinic has seen to date. other findings include the prevalence of preventative interventions including vaccinations, std testing and prenatal care. the poster presentation will present these and other impacts that the clinic has had on the health of the youth in the first year of the study. conclusions: ) the clinic has improved the health of ottawa streetyouth and will continue beyond the initial pilot project phase. ) this project demonstrates that with strong community partnerships, it is possible meet make healthcare more accessible for urban youth. right to health care campaign by s.j.chander, community health cell, bangalore, india. introduction: the people's health movement in india launched a campaign known as 'right to health care' during the silver jubilee year of the alma ata declaration of 'health for all' by ad in collahoration with the national human rights commission (nhrc). the aim of the campaign was to establish the 'right to health care' as a basic human right and to address structural deficiencies in the pubic health care system and unregulated private sector . . methods: as part of the campaign a public hearing was organized in a slum in bangalore. former chairman of the nhrc chaired the hearing panel, consisting of a senior health official and other eminent people in the city. detailed documentation of individual case studies on 'denial of access to health care' in different parts of the city was carried out using a specific format. the focus was on cases where denial of health services has led to loss of life, physical damage or severe financial losses to the patient. results: _fourte_en people, except one who had accessed a private clinic, presented their testimonies of their experiences m accessing the public health care services in government health centres. all the people, e_xcept_ one person who spontaneously shared her testimony, were identified by the organizations worki_ng with the slum dwellers. corruption and ill treatment were the main issues of concern to the people. five of the fourteen testimonies presented resulted in death due to negligence. the public health cen· n:s not only demand money for the supposedly free services but also ill-treats them with verbal abuse. five of these fourteen case studies were presented before the national human right commission. the poster sessions v nhrc has asked the government health officials to look into the cases that were presented and to rectify the anomalies in the system. as a result of the public hearing held in the slum, the nhrc identified urban health as one of key areas for focus during the national public hearing. cond#sion: a campaign is necessary to check the corrupted public health care system and a covetous private health care system. it helps people to understand the structure and functioning of public health care system and to assert their right to assess heath care. the public hearings or people's tribunals held during the campaign are an instrument in making the public health system accountable. ps- (a) violence among women who inject drugs nadia fairbairn, jo-anne stoltz, evan wood, kathy li, julio montaner, and thomas kerr background/object ives: violence is a major cause of morbidity and mortality among women living in urban settings. though it is widely recognized that violence is endemic to inner-city illicit drug markets, little is known about violence experienced by women injection drug users (!du). therefore, the present analyses were conducted to evaluate the prevalence of, and characteristics associated with, experiencing violence among a cohort of female idu in vancouver. methods: we evaluated factors associated with violence among female participants enrolled in the vancouver injection drug user study (vidus) using univariate analyses. we also examined self-reported relationships with the perpetrator of the attack and the nature of the violent attack. results: of the active iou followed between december , and may , , ( . %) had experienced violence during the last six months. variables positively associated with experiencing violence included: homelessness (or= . , % ci: . - . , p < . ), public injecting (or= . , % ci: . - . , p < . ), frequent crack use (or= . , % ci: . - . , p < . ), recent incarceration (or = . , % cl: . - . , p < . ), receiving help injecting (or = . , % cl: . - . , p < . ), shooting gallery attendance (or = . , % ci: . - . , p < . ), sex trade work (or = . , % cl: . - . , p < . ), frequent heroin injection (or= . , % cl: . - . , p < . ), and residence in the downtown eastside (odds ratio [or] = . , % ci: . - . , p < . ). variables negatively associated with experiencing violence included: being married or common-law (or = . . % ci: . - . , p < . ) and being in methadone treatment (or = . , % ci: . - . , p < . ). the most common perpetrators of the attack were acquaintances ( . %), strangers ( . %), police ( . %), or dealers ( . %). attacks were most frequently in the form of beatings ( . %), robberies ( . %), and assault with a weapon ( . %). conclusion: violence was a common experience among women !du in this cohort. being the victim of violence was associated with various factors, including homelessness and public injecting. these findings indicate the need for targeted prevention and support services, such as supportive housing programs and safer injection facilities, for women iou. introduction: although research on determinants of tobacco use among arab youth has been carried out at several ecologic levels, such research has included conceptual models and has compared the two different types of tobacco that are most commonly used among the lebanese youth, namely cigarette and argileh. this study uses the ecological model to investigate differences between the genders as related to the determinants of both cigarette and argileh use among youth. methodology: quantitative data was collected from youth in economically disadvantaged urban communities in beirut, the capital of lebanon. results: the results indicated that there are differences by gender at a variety of ecological levels of influence on smoking behavior. for cigarettes, gender differences were found in knowledge, peer, family, and community influences. for argileh, gender differences were found at the peer, family, and community l.evels. the differential prevalence of cigarette and argileh smoking between boys and girls s therefore understandable and partially explained by the variation in the interpersonal and community envi.ronment which surrounds them. interventions therefore need to be tailored to the specific needs of boys and girls. introduction: the objective of this study was to assess the relationship between parents' employment status and children' health among professional immigrant families in vancouver. our target communmes v poster sessions included immigrants from five ethnicity groups: south korean, indian, chine~e, ~ussian, and irani~ with professional degrees (i.e., mds, lawyers, engineers, ma?~ger~, and uru~ers ty professors) w h no relevant job to their professions and those who had been hvmg m the studied area at least for months. methodology: the participants were recruited by collaboration from three local community agencies and were interviewed individually during the fall of . ra#lts: totally, complete interviews were analyzed: from south-east asia, from south asia, from russia and other eastern europe. overall, . % were employed, . % were underemployed, % indicated they were unemployed. overall, . % were not satisfied with their current job. russians and other eastern europeans were most likely satisfied with their current job, while south-east asians were most satisfied from their life in canada. about % indicated that their spouses were not satisfied with their life in canada, while % believed that their children are very satisfied from their life in canada. in addition, around % said they were not satisfied from their family relationship in canada. while most of the responders ranked their own and their spouses' health status as either poor or very poor, jut % indicated that their first child's health was very poor. in most cases they ranked their children's health as excellent or very good. the results of this pilot study show that there is a need to create culturally specific child health and behavioral scales when conducting research in immigrant communities. for instance, in many asian cultures, it is customary for a parent either to praise their children profusely, or to condemn them. this cultural practice, called "saving face," can affect research results, as it might have affected the present study. necessary steps, therefore, are needed to revise the current standard health and behavioral scales for further studies by developing a new scale that is more relevant and culturally sensitive to the targeted immigrant families. metboda: database: national health survey (ministry of health www.msc.es). two thousand interviews were performed among madrid population ( . % of the whole); corresponded to older adults ( . % of the . million aged years and over). study sample constitutes . % ( out of ) of those older adults, who live in urban areas. demographic structure (by age and gender) of this population in relation to health services use (medical consultations, dentist visits, emergence services, hospitalisation) was studied using general linear model univariate procedure. a p . ), while age was associated with emergence services use ( % of the population: %, % and % of each age group) and hos~italisation ( % .oft~~ population: %, % and %, of each age ~oup) (p . ) was fou~d with respect to dennst v s ts ( % vs %), medical consultations ( % vs %), and emergence services use ( % vs %), while an association (p= . ) was found according to hospitalisation ( % vs %). age. an~ g~der interaction effect on health services use was not found (p> . ), but a trend towards bosp tal sanon (p= . ) could be considered. concl.uions: demographic structure of urban older adults is associated with two of the four health se~ices use studi~. a relation.ship ber_ween age. and hospital services use (emergence units and hospitalisanon), but not with ~ut-hosp tal sei:vices (medical and dentist consultations), was found. in addition ro age, gender also contnbutes to explam hospitalisation. . sexua experiences. we exammed the prevalence expenences relation to ethnic origin and other sociodemographic variables as wc i as y j die relation between unwanted sexual experiences, depression and agreuion. we did so for boys and prts separately. mdhods: data on unwanted sexual expcric:nces, depressive symptoms (ce.s-d), aggrc:uion (bohi-di and sociodemographic facron were collected by self-report quescionnairc:s administettd to students in the: nd grade (aged - ) of secondary schools in amsterdam, the netherlands. data on the nature ol unwanted sexual experiences were collected during penonal interviews by trained schoolnursn. ltaijtj: overall prevalences of unwanted sexual experiences for boys and girls were . % and . % respectively. unwanted sexual experiences were more often ttported by turkish ( . %), moroc· an ( . %) and surinamese/anrillian boys ( . %) than by dutch boys ( . %). moroccan and turkish girls, however, reported fewer unwanted sexual experiences (respectively . and . %) than durch girls did ( . %). depressive symptoms(or= . , cl= . - . ) covert agression ( r• . , cl• . - . ) and cmrt aggression (or= . , cl• . - . ) were more common in girls with an unwanted sexual experi· met. boys with an unwanted sexual experience reported more depressive symptoms (or= . ; cl• i . .l· . ) and oven agression (or= . , cl= . - . ) . of the reported unwanted sexual experiences rnpec· timy . % and . % were confirmed by male and female adolescents during a personal interview. cond sion: we ..:an conclude that the prevalence of unwanted sexual experiences among turkish and moroccan boys is disturbing. it is possible that unwanted sexual experiences are more reported hy boys who belong to a religion or culture where the virginity of girls is a maner of family honour and talking about sexuality is taboo. more boys than girls did not confirm their initial disdosurc of an lllwalltc:d sexual experience. the low rates of disclosure among boys suggcsu a necd to educ.:atc hcahh care providen and others who work with migrant boys in the recognition and repomng of exu.il ... iction. viramin a aupplc:tmntation i at .h'yo, till far from tafl'eted %. feedinit pracn~:n panku· lerty for new born earn demand lot of educatton ernpha a• cxdu ve hrealt fecdtnit for dnared rcnoj of months was observtd in only .s% of childrrn thoulh colckturm w. givm n rn% of mwly horn ct.ildrm. the proportion of children hclow- waz (malnounshrdl .con" a• h!jh •• . % anj "rt'i· acimy tc.. compared to data. mother's ~alth: from all is womm in ttprod~uvr •ill' poup, % were married and among marned w~ .\ % only w\"rt' u mic wmr cnntr.-:cruve mt h· odl % were married bdorc thc •ar of yean and % had thnr ftnc prcicnancy hcftitt dlt' •icr nf yean. the lt'f'vicn are not uutfactory or they arc adequate but nae unh ed opumally. of thote' l'h mothen who had deliverrd in last one year, % had nailed ntmaral eum nat on ira" oncc, .~o-... bad matt rhan four ttmn and ma ortty had heir tetanus toxotd tnin,"t or"'" nlht "'"'"· ljn r ned rn· win ronductrd . % dchvcnn and % had home deh\'t'oc'i. ~md~: the tervtcn unbud or u led are !tu than dnarame. the wr· l'kft provided are inadequate and on dechm reprcwnttng a looun t ~p of h hnto good coytti\#' ol wr· ncn. l!.ckground chanpng pnoriry cannoc be ruled out u °"" of thc coatnbutory bc f. ps-ii ia) dcpn:wioa aad anuccy ia mip'mu ia awccr._ many de wn, witco tui~bmjer. jack dekker, aart·jan lttkman, wim gonmc:n. and amoud verhoeff ~ a dutch commumry-bucd icudy thawed -moarh•·prc:yalm«i al . ' . kw anx · ay daorden and . % foi' dqrasion m anmttdam. nm .. p tficantly hlllhn than dwwhrft .. dw ~thew diffamca m pttyalcnca att probably rdarcd to tlk' largr populanoa of napaan ..\mturdam. <turkish %, moroccan %, and surinam % . lndttd. ic'wt'll ltudla hatt ~ ~ high prevalena rata among migrant poupi in rbe ncdwrlands. howc'ytt au ttlluchn iuffenod from wry low raporne rara, or med screnung talel thac lack a ~y yabdarcd ~ in order to study the prevalence of depression and anxiety, and the (barriers to) use of mental health care among the different ethnic groups the following study was recently conducted: . the study consisted of a two-step approach. the first step was mcl~ded m the ~ h ith survey of (ahs), and consisted of three screening scales for depression and aruaety (klo, g::q- and mhl- ). in this survey all respondents were asked_ permission for~ second app~ :' t consisted of a structured interview containing the cidi for aruaety and depression, and questtollllalres on health care seeking, amongst others. all respondents who gave permission for a second approachwere invited by jetter for a suuctured interview with multilingual interviewers at home at a preset date and time in the following week. . in total, dutch, turkish, moroccan and surinam respondents took part in the ahs and gave permission for a second approach. in the second step, fo~ ~ tur~h, m~roc can surinamese and dutch respondents, information from the extensive interview was available (res~nse rates between and % ). since the data collection was completed only recently (june ), prevalence estimates can be presented at the conference for the first time. we have shown that with this approach it is feasible to achieve an acceptable response rate in a study on mental health among migrants. therefore we expect that this study will provide reli· able estimates of depression and anxiety in the turkish, moroccan and surinam migrants in amstw! ~· for the first time. in addition, insight into mechanisms underlying the differences between and within ethnic groups and into barriers to mental health care will provide pretexts for the improvement of pre· vention and mental health care for migrant groups. this study aimed to determine spatial patterns of mortality and morbidity of five major health problems in an urban environment: homicides, pregnancy among adolescents ((< years old), asthma hospitalization among young children(< years old) and two mosquito-borne diseasesdengue and visceral leishmaniasis, during - . all events were obtained through the city health database and, subsequently, geoproccsscd using the address of residence and the geographical and administrative division of the municipality, composed by unit of planning (up), which in tum were formed, each one, by census tract units. two research questions were investigated: are there spatial patterns to the events dis· tribution, and moreover, are these patterns overlapping across space? we use thematic maps, index of comparative mortality/morbidity by up and the overlapped rank of the th worse up rates for each event. a spatial pattern of high rates of homicides, proportion of young mothers and hospitalization of asthma were overlapping in areas social and economically disadvantaged. for mosquito-borne diseases, high rates with great dispersion were found in unprivileged areas in contrast with very low rares among privileged ones. these results pointed toward a coexistence of heavier burden of diseases for those living in areas of the city where misery, poverty, lack of political public health may be modulating social health problems. a possible environmental intervention in one mosquito•bome disease might be playing a role in the occurrence of other. although with limitations, this study may provide useful information for a joint urban planning under the public perspective, articulated for use in health impact assessment. jalil safaei bdrod#aion: the association of socioeconomic status (ses), usually measured by income, and health status is an established result in bcalth studies. the poor and low income individuals have lower health sta· tus then_ those with higher incomes. in general. such finding has been usually obtained from sample surveys on speafic populations. a problem with many sample survey$ is that their results are not comparable aaoss ~ndaries as they may use different sampling methods, ask different questions, categorize the answers differently, or define groups differently. moreover, the sample data need to be standardized using the demographic: katurea of a ~ population. this study, however, uses the national population health survey (nphs) cycle public use mictodata files which is based on a common survey template ·~~three~ area in canada, namely montreal, toronto, and vancouver. it also utili .es the built-m stanclatdizaaon of the nphs data which accounts for its complex survey design. . ~:the stu~ usc:s two well-known measures of health inequalitythe relative index of meqaality and die concentranon indexto capture the extent of income related health inequality among poster sessions v urban female and male populations in each of the three metropolitan areas. personal income is classified into ten groups by the nphs with "no income" as the first group and "more than $ , " as the last. health status is measured by three variables -having a chronic condition (chc), self assessed health (sah), and health utility index (hui) -using appropriate indices. alternative formulations are used to calculate the standard deviations of the estimated or calculated measures. the findings of the study suggest that the measured health inequality depends on the health measure used. for chc and hui the measured inequality indices do indicate poorer health for lower income individulas, however, they are not statistically insignificant. health inequalities are more pronounced when health is measured by sah. the results do not support any systematic ranking of the three metropolitan areas in terms of health inequalities. they do not reveal any systematic pattern of inequality between men and women, either. conclusions: despite the use of highly aggregated nphs data, income related health disparities are observed in the three metropolitan areas in canada. this is more the case with self perceived (sah) health. such disparities are preventable and call for broader health policies that address poverty and low income among other social determinants of health. introduction: the analysis of health indicators under the spatial perspective is configured as an important instrument in the detection of intra-urban differentials. this study aimed to examine the spatial distribution of the births occurred in belo horizonte, in , analyzing the presence of spatial clusters of health indicators for newborns (rn) and their mothers, using data from the information system on live birth database (sinasc). method: for each covered area of the basic units of health (ubs), we calculated the proportion of: adolescent mothers, mothers with less than years of schooling, first pregnancy, mothers with four or more pregnancies, dead babies born on previous pregnancies, stillbirths, cesarean section, less than four prenatal care attendance, moderate and severe hypoxemia in the st and th minutes of life, low or very low birth weight. we used empiric bayesian methods for smoothing the estimates. for spatial analysis, the indicators obtained from the global moran (i) index and local indicators of spatial association (lisa) were used. maps were built to allow the visualization of the spatial clusters. in all analysis, significance statistics was considered p~ . . results: a total of , births of residents in belo horizonte were registered in i. the estimated bayesian proportions for the entire municipality was close to the one observed for all variables. analysis using lisa showed the presence of relevant spatial clusters for adolescent and low educated mothers, dead babies form previous pregnancies, cesarean section, low attendance to the prenatal care especially in area with low socio-demographic characteristics. three areas presented consistent clusters, with important spatial auto-correlation for almost all studied indicators. conclusion: the used methodology was configured as a great instrument of detection risk areas where clustering occurs. it can easily be incorporated in any surveillance system as a mechanism for controlling events related to births in the municipality. moreover, it can be applied to discriminate target areas for prompt public health interventions, such as improving health services access and the consolidation of better obstetric practices. introduction: gentrification, the displacement of low income and non-majority people out of longtime neighborhoods and residences is a global phenomenon. it has been identified as occurring in both developed and less developed countries and as inequality persists or increases, many communities are vulnerable to disruption and loss. while there may be some benefits to gentrification, these benefits are less likely to impact those who have been forced to move out of a gentrifying community or those who remain but economically stressed. . . . . this paper lays out a theoretical framework for dent fymg and ~ddressm~. the_ health consequences of gentrification on residents living in a community prior .to o.r durmg gent~ ~ cat. n. by drawing on the literature of housing, sociology, health and urban plannmg, t places genmf catt~n and neighborhood change into the context of other forces affecting th~ .hea.lth of vulnerable populations. it then proposes solutions to prevent or mitigate the impacts of genmf cat on. results: four main categories of consequences potentiallr re~ult from ~entr~fica~~n: !'°°r housing· related issues, spatial effects, mental health impacts and contr bunons to racial ~spanttes m heal~. the housing issues include increased susceptibility to asthma, lead exposure, allergiesl~topy an~. acetdents/ injuries. spatial effects include reduced access to health ~are, reduce~ access to obslttadinonal food sources, decreased physical activity, and increased obesity. the __ pnmary mental health effects_ :ire increased stress increased risk of depression and disruption of trad t onal support networks. in addinon to the above he~lth issues, gentrification has the potential to increase racial disparities in health by reduc· ing access to long term and multi-culturally experienced health care provide~s. conclusions: public health practice provides a framework for addressmg the health consequences of gentrification. in this context primary prevention would involve preventing gentrification in the first place along with a renewed commitment to helping distressed communities a~~ im_proving the quality ~f life for long term residents. the next layer of meeting the challenges of gentrification would be to assjst long rime residents to stay in a community and thus potentially allowing them to participate in the bene~ts of gentrification (such as better public services). only if all these efforts fail -and these other prevennon strategies must be a priority, public policy should then work to help people and instirutions move to other communities through grants and the provision of alternative safe affordable housing and neighborhoods. sarah romans, marsha cohen, and tonia forte lnh'odlletion: there has been sustained interest in urban rural (ur) differences in mental health over the last years of epidemiological research, with most studies reporting higher urban rates of mor· bidity, particularly when psychotic disorders have been studied. most recently, in britain, urban rates of non-psychotic disorder were greater than rural and semi-rural rates, both before and after the more adverse circumstances of urban dwellers were considered (paykel et al ) . surprisingly, there were no ur differences in help seeking. in canada, wang ( ) found greater urban rates for major depression only after he controlled for the confounding effects of race, immigration, employment and marital status, a result reminiscent of work from the us (blazer et ) . rural participants were less likely to have sought help for their mental health problems. in this study, we sought to examine urban/rural differences in rates of depression and help seeking in canada. method; data came from the canadian community health survey . , a community survey conducted by statistics canada of people aged and older, with the total sample size of , respon· dents, % response. analyses used weighted data; differences were assessed by chi-squared. ra.its: bivariate cross-tabulations showed a modest increase in month depression rates for urban ( . %) over rural ( . %, p= . ) dwellers; there were no ur differences when the sample was examined separately by gender and age group ( - , - , - ) . in general, more urban ( . %) than rural people ( . %, p= . ) had sought mental health treatment in the past year. there was no ur difference in helping seeking amongst those with depression (u . %, r . % ns). amongst the whole population, helping seeking was gendered with more urban men accessing help ( . %) than rural men ( . %, p= . ); this did not apply for women ( . % vs . % p= . ). ~ons: the urban-rural demographic continues to generate intriguing findings, even recently when internal migration is common and people can seek out the environment most conducive to their health, ~th physical and mental. people with depression are a disadvantaged, frequently stigmatized group, with ~r quality of life a_nd often impaired function. unlike many other factors associated wi~h urban or rural hfe per se, depression can be treated. the low help seeking rates is a cause for concern, m both the ur~n and_ rural populations. it behooves researchers, policy makers and service planners to ensutt effective services are available for both humane and economic reasons. methods: using united states census income data, we assigned the manhattan community districts to two major socioeconomic groups, manhattan i and ii. manhattan i is composed of community districts with average household incomes above the median for new york city; manhattan ii is those below. with public new york city department of health death records and us census data, we calculated a "standard" new york city population and estimated mortality rate distributions for manhattan i and ii. we then compared these age-adjusted actual mortality distributions with a standard t-test. results: we explored premature deaths using several cut-off points (before the ages of , , and ), and with subcomparisons for males and females. every comparison showed the wealthier area, manhattan i, to have significantly lower premature mortality rates than the lower income manhattan ii. further, we compared age-adjusted mortality rates among the city's five boroughs, and found no significant differences based on local geography alone. conclusions: these findings suggest that in manhattan, characterized by its extremes of wealth and poverty, health status, as measured by premature mortality, does vary significantly with the local income level. in manhattan, the relative average income by community district varies as much as : . this ratio is greater than that found in the other cities we have studied: for example, the range among tokyo's kus is half that in manhattan, or about : . paris has shown the longest life expectancy and changing premature mortality rates. from our preliminary work, we expect to find less variation in premature mortality rates in comparable cities. this study will continue to explore the relationship of premature mortality rates and life expectancy to income levels and different health systems among wcp cities with a view to measuring health policy options. introduction: according to the world health organization (who), smoking-related illness is currently the world's second major cause of death, currently responsible for one out of ten adult deaths worldwide. the who's framework convention on tobacco control (fctc) aims to reduce tobaccorelated disease and deaths by changing national public policies. mexico, which, according to the who, had smoking prevalences of % among adults in and % among health care providers (hcps) in , ratified the fctc in . objective: to examine knowledge of and attitudes towards cigarette smoking and smoking cessation among hcps, and clinical practices regarding smoking cessation. methods: in june , a convenience sample of hcps from one public clinic in urban oaxaca, mexico, part of mexico's national network of public health care clinics, were interviewed in spanish using a verbally administered questionnaire that was standard among all participants. during primary care outpatient visits, hcps were observed treating patients to assess the relative importance of smoking cessation as a health care priority. results: of the hcps interviewed, including ten physicians, three nurses, and five medical students, % reported smoking regularly. all hcps reported assessing patients' history of smoking, knowledge of the health risks associated with smoking, and feeling qualified to discuss these risks with patients. all hcps reported counseling patients who currently smoked to quit. all hcps reported recommending nicotine replacement therapy (eg., patch and/or gum) and/or behavioral therapy (eg., psychologist, support groups) to patients who smoked. all hcps reported that there was no government funding for smoking cessation, and that all costs associated with smoking cessation were patients' out-of-pocket expenses. observation of hcp interaction with patients revealed that hcps always inquired about smoking history with new patients and rarely inquired about smoking history with returning patients. hcps were not observed counseling patients who reported current smoking on smoking cessation methods and its benefits. observation of the clinical environment suggested a focus on preventative child health (eg., immunization, water-borne illnesses), family planning, and chronic diseases (eg., diabetes, hypertension). conclusions: while the mexican government has made smoking cessation a public health priority and hcps report addressing smoking cessation, observation of hcps suggests: ) smoking status is assessed only in new patients; and ) smoking cessation methods are not addresse~. observ_atio~ of hcps and the clinical environment in a public clinic in oaxaca suggests that smoking cessation s of lower priority than other heath care issues. p - (a) urban agriculture and food and nutrition security in kampala, uganda fiona yeudall, renee sebastian, abdelrahman lubowa, selahadin ibrahim, and donald cole introduction: urban agriculture is an important livelihood strategy contributing to household food security by increasing access and availability to food in urban settings (koc et al., ) . the purpose of poster sessions v rhis study was to examine relationships between child nutritional securiry outcomes, household food security, and urban agriculture activiries in kampala, uga~da. . . questionnaires assessing socio-demographic, farmmg and household food secunry (hfsi characreristics were administered to households. food diversiry was ~lculate~ from ~e number of foods consumed over hours for one child ( - years) per household. heigh~ weight,. nud-upper·ann· circumference (muac) and tricep skinfolds (tsf) were measured for the mdex child. z-sc.ores for height-for·age (haz), weighr-for-age (waz) and body mass index (zbmi) were ~~ulated usmg cen· rres for disease control and prevenrion reference data. z-scores for body composition measures were calculated using nhanes i and ii data for african americans. the lms method was used to c~.t for skewed z·score indices. all dara was checked for normaliry and univariable and backward mulnvanablc linear regression analysis conducted. ruwlts: household food securiry was significantly associated with wealth (b= . , p< 'a acre were more dependenr on assets for hfs. although sex of head of household was ~ot related to j-:ifs, it modi· fied relationships in rhar female headed households had greater food securtry when fai:mmg less than , acre compared ro male headed households, and vice versa. hfs was significantly associated with food diversiry (s= . , p). urbanization, especially in developing countries, has substantially increased the vulnerability of rhe mass of low-income urban dwellers. the livelihoods and quality of life for many of the poor espe· cially in larin america, asia, and africa, have deteriorated significantly over the years. urban areas are increasingly unable to provide for their populations, resulting in poverry, massive unemploymenr, job cuts, poor housing, lack of or poor public services, and a compromised health status. botswana, a country rhat lies in the sourhern parr of africa, has had its share of urban problems such as rhe mush· rooming of squarters and low-income urban sertlements. despite efforts to address the substandard living conditions in low-income urban areas, these problems have continued to grow. these living con· diuons are porenrially stressful to rhe residenrs and likely affects their health. the primary aim of the udy wa to examine the complex relationship between communiry-level stressors and interveners and health-related quality of life among residents of low-income neighborhoods in francistown, botswana. u i"" a croa -icctional quantitative design (both descriptive and explanatory) and using primarily cloae-mded interview• with a random sample of residents, this study examined the role of chrome life trnson and environmental quality on overall health status qualiry of life) and the physical, psy· chological and level of independence domains of health. the major hypothesis of the study was that community-levrl stre sor would influence health-related quality of life and that social capital would moderate these relationships. findings indicate that neighborhood quality is a powerful predictor of healrh tatu rhan socioeconomic status and individual life stressors. social capital was also found to he a ificant positive predictor of healrh and also moderator of structural factors. social capital moderated the effects of low environmental quality on level of indrpendence and on physical health outcomn, but nor on psychological and global health outcomes. these findings suggest that as the environment get betttr. stresson are reduced, hence promoting berter health outcomes. the study ends with implication• for social justice, public health and social work practice, and research, focusing mostly on the ~ole of social capital and the environmental quality in predicting health outcomes. spt· cafically • anenhon should be focused on political and civic society's commitment for social justice and poveny alleviation, ~uction of the threat of insecuriry and violence; cultivating social capital and good governance; and improving the health and social environments, especially housing and environ· mental aiutanon to name a few. urban and other uprisings by non-elites that lead to transitions, can disrupt sexual and injection "risk" networks that transmit infectious diseases by changing mixing patterns. they can also weaken urban social networks, their associated protective norms and their informal social control mechanisms which can lead to increased sexual and drug risk behaviors and violence (fullilove ; wallace & wallace , aral , friedman & reid hankins et al ) . for example, the revolution and transition to theocratic rule, and subsequent urban and national conflicts, have been followed by many urban youth in iran engaging in clandestine high-risk sexual and drug behaviors. in palestine, conflicts and restrictions on movement have led to increased fatalities from chronic diseases due to limited access to hospitals and modern medical facilities (union of palestinian medical relief committees); and heroin use and violence-related blood exposure have also increased. social movements "from below" that are rooted both in urban social network dynamics and in underlying patterns of injustice can have both protective and risky effects. for example, the social movements that led to the collapse of the ussr and its dependent governments in other countries-with subsequent increases in sex trade, alcoholism, drug use, tuberculosis, hiv, stis, and mortality in many localities-were based originally on such city-based movements in eastern europe. their impacts on health were mediated by urban social dynamics and structures. some urban social movements have improved health by prevent· ing the spread of hiv, hepatitis and other diseases. examples include movements of (a) gays and lesbians and (b) drug users. these have been rooted in social networks that overlap with risk networks. theories of urban health should include social conflict as a core concept. mechanisms that generate conflicts and the pathways by which conflicts affect health should be a major part of urban health research agendas. p - (c) demographic characteristics of people seen with tuberculosis in lagos state university teaching hospital (lasuth) chest clinic john bako, adewale akeredolu, and wale alabi tuberculosis has become a resurgent public health problem in recent times in the world. because resources are limited, control programmes frequently must target population at greatest risk. the purpose of this study was to study the demographic characteristics of people seen with tuberculosis in lagos state university teaching hospital. a total of patients who have been both radiologically and bacteriologically confirmed tuberculosis patients were used for this study between january and march. ( %) were males, while ( %) were females. notable risk factors among patients with tuberculosis were overcrowding ( . % ), homelessness ( . %) cigarette smoking ( . % ), alcoholism ( . %), non vaccination ( %), secondary contact ( . %) and poor knowledge ( . l 'x,). man· agement history patterns among the patients were herbs ( . 'yo), orthodox medicine ( .h . .l'x.). intervention targeting early-identified groups may be an effective way to reduce the incidence of tuber· culosis. such intervention should focus on health education, modification of life style and improvement of standard of living. p - (c) profiles in urban health in cities of the americas in the countries of the americas, there is an increasing migration of national and international populations to urban centers. this presentation will focus on some of the issues created by this influx of populations, the ways that cities in countries are dealing with them, and the efforts to promote local participation and solutions in management and decision-making. the methodology used to collect this information has been to draw upon and analyze information produced by the mayor's and ministry of health and development offices in each of the cities under consideration. an analysis of the impact of urbanization on health and health determinants will be presented. the information covers issues such as health status by geographic areas within the cities, highlighting issues such as marginality, barriers and physical, economic and cultural constructs and inequities in the delivery of and access to essential services (such as health, education, water, and basic sanitation). issues of governance and citizen participation will be highlighted to provide insight in~o the balance of power and mechanisms for decision-making at the local level. part of the analysis will show the relationship between democratic processes and social participation. public ~olicies will be reviewed to indicate those that are most beneficial in promoting health and overcoming barriers to it, as well as ways of capitalizing on local assets and resources. final~y, evidence of effectiveness of various strategies will be indicated. the presentation will conclude wuh suggesuons for future strategic directions to improve the quality of life and the promotion of health in large urban centers of the americas. introduction: much of the illicit drug in mexico is concentrated in northern border areas. the mile border between the u.s. and mexico is also characterized by migration; the border crossing between tijuana, baja california, mexico and san diego, california, u.s.a. is rep~rt~dl~ the busiest land border crossing in the world. we attempt to describe the migration scene among m ect on drug users (idus) m tijuana and investigate service needs. methods: migration trends were investigated in a cross-sectional study conducted from february to june among idus in tijuana. enrollment criteria included informed consent, being years or older, and having injected drugs within the prior month. subjects were recruited by respondent-dnven sampling and were administered a quantitative survey and serology for hiv, hcv, and syphilis. logistic regression was used to compare idus who had migrated to the u.s. versus those who had not. results: of idus enrolled, % were male and median age and age at first injection were and , respectively. drug combinations injected most frequently in the past months were heroin ( % and crystal methamphetamine mixed with heroin ( %). of those enrolled, responded to quesnons on migration and drug treatment and were included in this analysis. although % had resided in tijuana for at least years, % of users were born outside of baja california. working outside of mexico was common, with % working abroad in the last years ( % in u.s.), and % in the past year. in the last months, % of idus had crossed the border to the u.s., with % crossing at least once per month. those working outside of mexico in the past year were less likely to have ever received substance abuse treatment, [ % vs. %, or . , ] and were marginally less likely to have received drug treatment in the past months [ % vs. %, or . , % ci ( . - . )]. drug use patterns, age and gender did not differ between migrants and non-migrants, although migrants were more likely to report being in need of substance abuse treatment ( % vs. %, respectively). conclusions: migration is common among idus in tijuana. maintaining drug treatment regimens and determining how to best target education and services to a highly mobile population pose challenges to officials on both sides of the border. these data underscore the need to develop coordinated binational prevention and treatment efforts. introduction: despite the expanding literature on the important role public policy plays in influencing the broader determinants of the public\'s health, profound differences exist among jurisdictions in rhe attention placed upon such activities. we take an international perspective on health by examining rhe d?minant public _health paradigms of canada, usa, uk, and sweden and exploring how these paradigms shape public health practice. _method: we carefully analyze governmental and public health agencies documents to discern ~he dommant para~igms driving public health approaches and practices. we also consider the unique paht · cal and economic contexts within each nation and consider how these contexts drive public health pahcy and approaches. . . ~u~: the canadian and usa public health communities -with some exceptions --focus upon m~ividuahzed approaches to risk management. in contrast, the uk and swedish public health scenes are oriented toward broader approaches to health determinants. we find that the extent to which govern· ments, public health agencies and public health workers concern themselves with public policy approaches £<_> ~ddress ~ro.ad~r .determinants of health depends upon the particular health parad'.~ adhered. ~o withm each urisd ctton. and whether a paradigm is adopted depends upon the ideologi~a and pol~ncal context of each nation. nations such as sweden that have a long tradition of public policies promonng social jus~ce an~ equity are naturally receptive to evolving population health concepts. '[he usa represen~ a ~bey en~ro~~t where such is~ues are clear!~ subordinate. ., our findings mdicate that there s a strong political component that influences pubh ~ealth a~proaches and practi~ within the jurisdictions examined. the implications are that those seek· m~ to raise the broader detennmants of the public's health should work in coalition to raise these issues with non-health organizations and age · ca d d th · - badrgrollnd: in developed countries, social inequalities in health have endured or even worsened comparatively throughout different social groups since the s. in france, a country where access to medical and surgical care is theoretically affordable for everyone, health inequalities are among the high· est in western europe. in developing countries, health and access to care have remained critical issues. in madagascar, poverty has even increased in recent years, since the country wenr through political crisis and structural adjustment policies. objectives. we aimed to estimate and compare the impact of socio· economic status but also psychosocial characteristics (social integration, health beliefs, expectations and representation, and psychological characteristics) on the risk of having forgone healthcare in these dif· fercnt contexts. methods: population surveys conducted among random samples of households in some under· served paris neighbourhoods (n= ) and in the whole antananarivo city (n= ) in , using a common individual questionnaire in french and malagasy. reslllts: as expected, the impact of socioeconomic status is stronger in antananarivo than in paris. but, after making adjustments for numerous individual socio-economic and health characteristics, we observed in both cities a higher (and statically significant) occurrence of reponed forgone healthcare among people who have experienced childhood and/or adulthood difficulties (with relative risks up to and .s respectively in paris and antananarivo) and who complained about unhealthy living conditions. in paris, it is also correlated with a lack of trust in health services. coneluions: aside from purely financial hurdles, other individual factors play a role in the non-use of healthcare services. health insurance or free healthcare seems to be necessary hut not sufficienr to achieve an equitable access to care. therefore, health policies must not only focus on the reduction of the financial barriers to healthcare, but also must be supplemented by programmes (e.g. outreach care ser· vices, health education, health promotion programmes) and discretionary local policies tailored to the needs of those with poor health concern .. acknowledgments. this project was supported by the mal>io project and the national institute of statistics (instat) in madagascar, and hy the development research institute (ird) and the avenir programme of the national institute of health and medical research (inserm) in france. for the cities of developing countries, poverty is often described in terms of the living standard~ of slum populations, and there is good reason to believe that the health risks facing these populations are even greater, in some instances, than those facing rural villagers. yet much remains to be learned ahour the connections between urban poverty and health. it is not known what percentage of all urban poor live in slums, that is, in communities of concentrated poverty; neither is it known what proportion of slum residents are, in fact, poor. funhermore, no quantitative accounting is yet available that would sep· arare the health risks of slum life into those due to a househoid•s own poverty and those stemminic from poveny in the surrounding neighborhood. if urban health interventions are to be effectively targeted in developing countries, substantial progress must be made in addressing these cenrral issues. this paper examines poverty and children's health and survival using two large surveys, one a demographic and health survey fielded in urban egypt (with an oversampling of slums) and the other a survey of the slums of allahabad, india. using multivariate statistical methods. we find, in both settings: ( substan· rial evidence of living standards heterogeneity within the slums; ( strong evidence indicating that household-level poverty is an imponant influence on health; and ( ) staristically significant (though less strong) evidence that with household living standards held constant, neighborhood levels of poverty adversely affect health. the paper doses with a discussion of the implications of these findings for the targeting of health and poverty program interventions. p - (a) urban environment and the changing epidemiological surfacr. the cardiovascular ~ &om dorin, nigeria the emergence of cardiovascular diseases had been explained through the concomitants o_f the demographic transition wherein the prevalent causes of morbidity and monality ~hangr pr~mmant infectious diseases to diseases of lifestyle or chronic disease (see deck, ) . a ma or frustration m the v poster sessions case of cvd is its multifactural nature. it is acknowledged that the environment, however defined is the d · f · t' b tween agents and hosts such that chronic disease pathogenesis also reqmre a me an o mterac ion e . spatio-temporal coincidence of these two parties. what is not clear is which among ~ever~( potennal fac· · h b pace exacerbate cvd risk more· and to what extent does the ep dem olog cal trans · tors m t e ur an s ' . . . . tion h othesis relevant in the explanation of urban disease outlook even the developmg cities like nigeri~: thesis paper explorer these within a traditional city in nigeria. . . . the data for the study were obtained from two tertiary level hospitals m the metropolis for years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the data contain reported cases of cvd in the two facilities for the period. adopting a series of parametric and non-parametric statistics, we draw inferences between the observed cases of cvds and various demographic and locational variables of the patients. findings: about % of rhe cases occurred in years ( ) ( ) ( ) coinciding with the last year of military rule with great instability. . % occurred among male. . % also occurred among people aged - years. these are groups who are also likely to engage in most stressful life patterns. ~e study also shows that % of all cases occurred in the frontier wards with minor city areas also havmg their •fair' share. our result conformed with many empirical observation on the elusive nature of causation of cvd. this multifactoral nature had precluded the production of a map of hypertension that would be consistent with ideas of spatial prediction. cvd -cardiovascular diseases. mumbai is the commercial capital of india. as the hub of a rapidly transiting economy, mumbai provides an interesting case study into the health of urban populations in a developing country. with high-rise multimillion-dollar construction projects and crowded slums next to each other, mumbai presents a con· trast in development. there are a host of hi-tech hospitals which provide high quality care to the many who can afford it (including many westerners eager to jump the queue in their healthcare systems-'medical tour· ism'), at the same time there is a overcrowded and strained public healthcare system for those who cannot afford to pay. voluntary organizations are engaged in service provision as well as advocacy. the paper will outline role of the voluntary sector in the context of the development of the healthcare system in mumbai. mumbai has distinct upper, middle and lower economic classes, and the health needs and problems of all three have similarities and differences. these will be showcased, and the response of the healthcare system to these will be documented. a rising hiv prevalence rate, among the highest in india, is a challenge to the mumbai public healthcare system. the role of the voluntary sector in service provision, advocacy, and empowerment of local populations with regards to urban health has been paramount. the emergence of the voluntary sector as a major player in the puzzle of urban mumbai health, and it being visualized as voices of civil society or communiry representatives has advantages as well as pitfalls. this paper will be a unique attempt at examining urban health in india as a complex web of players. the influence of everyday socio·polirical-cultural and economic reality of the urban mumbai population will be a cross cutting theme in the analysis. the paper will thus help in filling a critical void in this context. the paper will thus map out issues of social justice, gender, equiry, effect of environment, through the lens of the role of the voluntary sector to construct a quilt of the realiry of healthcare in mumbai. the successes and failures of a long tradi· tion of the active advocacy and participation of the voluntary sector in trying to achieve social justice in the urban mumbai community will be analyzed. this will help in a better understanding of global urban health, and m how the voluntary sector/ngos fir into the larger picture. ba~und: o~er. half _of n~irobi's . million inhabitants live in illegal informal settlements that compose yo of the city s res dent al land area. the majority of slum residents lack access to proper san· iranon and a clean and adequate water supply. this research was designed to gain a clearer understand· mg of what kappr · · · h f . . opnate samtanon means or the urban poor, to determine the linkages between gender, hvehhoods, and access to water and sanitation, and to assess the ability of community sanitation blocks to meet water and sanitation needs in urban areas. m~tbojs_: _a household survey, gender specific focus groups and key informant interviews were conducted m maih saba, a peri-urban informal settlement. qualitative and quantitative research tools were u~ to asses~ the impact and effectiveness of community sanitation blocks in two informal settlements. results ropna e samtarmn me u es not only safe and clean latrines, but also provision ° adequate drainage and access to water supply for cleaning of clothes and homes. safety and cleanliness poster sessions v were priorities for women in latrines. levels of poverty within the informal settlements were identified and access to water and sanitation services improved with increased income. environmental health problems related to inadequate water and sanitation remain a problem for all residents. community sanitation blocks have improved the overall local environment and usage is far greater than envisioned in the design phase. women and children use the blocks less than men. this is a result of financial, social, and safety constraints. the results highlight the importance a need to expand participatory approaches for the design of water and sanitation interventions for the urban poor. plans need to recognize "appropriate sanitation" goes beyond provision of latrines and gender and socioeconomic differences must be taken into account. lessons and resources from pilot projects must be learned from, shared and leveraged so that solutions can be scaled up. underlying all the challenges facing improving water and sanitation for the urban poor are issues of land tenure. p - (c) integrating tqm (total quality management), good governance and social mobilization principles in health promotion leadership training programmes for new urban settings in countries/ areas: the prolead experience susan mercado, faren abdelaziz, and dorjursen bayarsaikhan introduction: globalization and urbanization have resulted in "new urban settings" characterized by a radical process of change with positive and negative effects, increased inequities, greater environmental impacts, expanding metropolitan areas and fast-growing slums and vulnerable populations. the key role of municipal health governance in mitigating and modulating these processes cannot be overemphasized. new and more effective ways of working with a wide variety of stakeholders is an underpinning theme for good governance in new urban settings. in relation to this, organizing and sustaining infrastructure and financing to promote health in cities through better governance is of paramount importance. there is a wealth of information on how health promotion can be enhanced in cities. despite this, appropriate capacity building programmes to enable municipal players to effectively respond to the challenges and impacts on health of globalization, urbanization and increasing inequity in new urban settings are deficient. the who kobe centre, (funded by the kobe group( and in collaboration with regional offices (emro, searo, wpro) with initial support from the japan voluntary contribution, developed a health promotion leadership training programme called "prolead" that focuses on new and autonomous structures and sustainable financing for health promotion in the context of new urban settings. methodology: country and/or city-level teams from areas, (china, fiji, india, japan, lebanon, malaysia, mongolia, oman, philippines, republic of korea, tonga and viet nam) worked on projects to advance health promotion infrastructure and financing in their areas over a month period. tools were provided to integrate principles of total quality management, good governance and social mobili .ation. results: six countries/areas have commenced projects on earmarking of tobacco and alcohol taxes for health, moblization of sports and arts organizations, integration of health promotion and social health insurance, organizational reforms, training in advocacy and lobbying, private sector and corporate mobilization and community mobilization. results from the other six areas will be reported in ..;obcr. conclusions: total quality management, good governance and social mobilization principles and skills are useful and relevant for helping municipal teams focus on strategic interventions to address complex and overwhelming determinants of health at the municipal level. the prolead training programmes hopes to inform other processes for building health promotion leadership capacity for new urban settings. the impact of city living and urbanization on the health of citizens in developing countries has received increasing attention in recent years. urban areas contribute largely to national economies. however, rapid and unplanned urban growth is often associated with poverty, environmental degradation and population demands that outstrip service capacity which conditions place human health at risk. local and national governments as well as multi national organizations are all grappling with the challenges of urbanization. with limited data and information available, urban health characteristics, including the types, quantities, locations and sources in kampala, are largely unknown. moreover, there is n? basis for assessing the impact of the resultant initiatives to improve health ~onditions amo~g ~o": ": um ties settled in unplanned areas. since urban areas are more than the aggregation ?f ~?pie w~th md_ v dual risk factors and health care needs, this paper argues that factors beyond the md v dual, mcludmg the poster sessions v · i d h · i · ment and systems of health and social services are determinants of the health soc a an p ys ca environ . of urban populations. however, as part of an ongoing study? ~s pape~ .addresses the basic concerns of urban health in kampala city. while applying the "urban hvmg conditions and the urban heal~ pen· alty" frameworks, this paper use aggregated urban health d~ta t~ explore the role of place an~ st tu· tions in shaping health and well-being of the population m kampala by understanding how characteristics of the urban environment and specific features of the city are causally related to health of invisible and forgotten urban poor population: results i~dica~e that a .range o~ urb~n he~l~h hazards m the city of kampala include substandard housing, crowdmg, mdoor air poll.ut on, msuff c ent a~d con· taminated water, inadequate sanitation and solid waste management services, vector borne .diseases, industrial waste increased motor vehicle traffic among others. the impact of these on the envtronment and community.health are mutually reinforcing. arising out of the withdra"'.al of city pl~nning systems and service delivery systems or just planning failure, thousands of people part cularl~ low-mc~me groups have been pushed to the most undesirable sections of the city where they are faced with ~ va_r ety ~f envj· ronmental insults. the number of initiatives to improve urban health is, however, growing mvolvjng the interaction of many sectors (health, environment, housing, energy, transportation and urban planning) and stakeholders (local government, non governmental organizations, aid donors and local community groups). key words: urban health governance, health risks, kampala. introduction: the viability of urban communities is dependent upon reliable and affordable mass transit. in particular, subway systems play an especially important role in the mass transit network, since they provide service to vast numbers of ridersseven of the subway systems worldwide report over one billion passenger rides each year. surprisingly, given the large number of people potentially affected, very little is known about the health and safety hazards that could affect both passengers and transit workers; these include physical (e.g., noise, vibration, accidents, electrified sources, temperature extremes), biological (e.g., transmission of infectious diseases, either through person-to-person spread or vector-borne, for example, through rodents), chemical (e.g., exposure to toxic and irritant chemicals and metals, gas emissions, fumes), electro-magnetic radiation, and psychosocial (e.g., violence, workstress). more recently, we need to consider the threat of terrorism, which could take the form of a mass casualty event (e.g., resulting from conventional incendiary devices), radiological attack (e.g., "dirty bomb"), chemical terrorist attack (e.g., sarin gas), or bioterrorist attack (e.g., weapons grade anthrax). given the large number of riders and workers potentially at risk, the public health implications are considerable. methods: to assess the hazards associated with subways, a structured review of the (english) litera· ture was conducted. ruults: based on our review, non-violent crime, followed by accidents, and violent crimes are most prevalent. compared to all other forms of mass transit, subways present greater health and safety risks. however, the rate of subway associated fatalities is much lower than the fatality rate associated with automobile travel ( . vs. . per million passenger miles), and cities with high subway ridership rates have a % lower per capita rate of transportation related fatalities than low ridership cities ( . versus . annual deaths per , residents). available data also suggest that subway noise levels and levels of air pollutants may exceed recommended levels. . ~: there is a paucity of published research examining the health and safety hazards associated with subways. most of the available data came from government agencies, who rely on passively reported data. research is warranted on this topic for a number of reasons, not only to address important knowled~ gaps, but also because the population at potential risk is large. importantly, from an urban perspecnve, the benefits of mass transit are optimized by high ridership ratesand these could be adversely affu:ted by unsafe conditions and health and safety concerns. veena joshi, jeremy lim. and benjamin chua ~ ~rban health issues have moved beyond infectious diseases and now centre largely on chrome diseases. diabetes is one of the most prevalent non-communicable diseases globally. % of adult ¥ benefit in providing splash pads in more parks. given the high temperature and humidity of london summers, this is an important aspect and asset of parks. interviewed parents claimed to visit city parks anywhere between to days per week. corrduion: given that the vast majority of canadian children are insufficiently active to gain health benefits, identifying effective qualities of local parks, that may support and foster physical activity is essential. strategies to promote activity within children's environments are an important health initiative. the results from this study have implications for city planners and policy makers; parents' opinions of, and use of city parks provides feedback as to the state current local parks, and modifications that should be made for new ones being developed. this study may also provide important feedback for health promoters trying to advocate for physical activity among children. introdt clion: a rapidly increasing proportion of urban dwellers in africa live below the poverty line in overcrowded slums characterized by uncollected garbage, unsafe water, and deficient sanitation and overflowing sewers. this growth of urban poverty challenges the commonly held assumption that urban populations enjoy better health than their rural counterparts. the objectives of this study are (i) to compare the vaccination status, and morbidity and mortality outcomes among children in the slums of nairobi with rural kenya, and (ii) to examine the factors associated with poor child health in the slums. we use data from demographic and health survey representative of all slum settlements in nairobi city carried out in by the african population & health research center. a total of , women aged - from , households were interviewed. our sample consists of , children aged - months. the comparison data are from the kenya demographic and health survey. the outcomes of interest include child vaccination status, morbidity (diarrhea, fever and cough) and mortality, all dichotomized. socioeconomic, environmental, demographic, and behavioral factors, as well as child and mother characteristics, are included in the multivariate analyses. multilevel logistic regression models are used. l'nlimin ry rest lts: about % of children in the slums had diarrhea in the two weeks prior to the survey, compared to % of rural children. these disparities between the urban poor anj the rural residents are also observed for fever ( % against %), cough ( % versus %), infant mortality ( / against / ), and complete vaccination ( % against %). preliminary multivariate results indicate that health service utilization and maternal education have the strongest predictive power on child morbidity and mortality in the slums, and that household wealth has only minor, statistically insignificant effects. conclruion: the superiority of health of urban children, compared with their rural counterparts, masks significant disparities within urban areas. compared to rural residents, children of slum dwellers in nairobi are sicker, are less likely to utilize health services when sick, and stand greater risk to die. our results suggest policies and programs contributing to the attainment of the millennium development goal on child health should pay particular attention to the urban poor. the insignificance of socioeconomic status suggests that poor health outcomes in these communities are compounded by poor environmental sanitation and behavioral factors that could partly be improved through female education and behavior change communication. introduction: historic trade city surat with its industrial and political peace has remained a center of attraction for people from all the comers of india resulting in to pop.ulatio~ explosio~ a~d stressed social and service infrastructure. the topography,dimate and demographic profile of the city s threat to the healthy environment. aim of this analysis is to review the impact of managemt'nt reform on health indicators. method: this paper is an analysis of the changing profile of population, sanitary infr~s~rucrure, local self government management and public health service reform, secondary health stat st cs data, health indicator and process monitoring of years. . . health of entire city and challenge to the management system. plague outbr~ak ( ) was the turning point in the history of civic service management including p~blic ~e~lth service management. ~ocal self government management system was revitalized by reg~lar_ field v s ts o~ al~ cadre~, _decentraltzanon of power and responsibility, equity, regular vigilant momtormg, commumcanon facility, ream_approach and people participation. reform in public health service management was throu_gh stan~~rd zed intervention protocol, innovative intervention, public private partnership, community part c panon, academic and service institute collaboration and research. sanitation service coverage have reached nearer to universal. area covered by safe water supply reached to %( ) from % ( ) and underground drainage to % ( ) from % ( ) the overhauling of the system have reflected on health indicators of vector and water born disease. malaria spr declined to . ( ) from . 'yo(! ) and diarrhea case report declined to ( ) from ( ). except dengue fever in no major disease outbreaks are reported after . city is recipient of international/national awards/ranking for these achievements. the health department have developed an evidence and experience based intervention and monitoring system and protocol for routine as well as disaster situation. the health service and management structure of surat city have emerged as an urban health model for the country. introduction: the center for healthy communities (chc) in the department of family and com· munity medicine at the medical college of wisconsin developed a pilot project to: ) assess the know· ledge, attitudes, and behaviors of female milwaukee public housing residents related to breast cancer; develop culturally and literacy appropriate education and screening modules; ) implement the developed modules; ) evaluate the modules; and ) provide follow-up services. using a community-based participatory research model the chc worked collaboratively with on-site nurse case management to meet these objectives. methods: a "breast health kick off event" was held at four separate milwaukee public housing sites for elderly and disabled adults. female residents were invited to complete a -item breast health survey, designed to accommodate various literacy levels. responses were anonymous and voluntary. the survey asked women about their previous physical exams for breast health, and then presented a series of state· ments about breast cancer to determine any existing myths. the final part gathered information about personal risk for breast cancer, the highest level of education completed, and whether the respondents h;td ever used hormone replacement therapy and/or consumed alcohol. responses were collected for descriptive analysis. results: a total of surveys (representing % of the total female population in the four sites) were completed and analyzed. % reported that they had a physical exam in the previous rwo years. % of respondents indicated they never had been diagnosed with breast cancer. % reported having had a mammogram and % having had a clinical breast exam. those that never had a mammogram reported a fear of what the provider would discover or there were not any current breast problems ro warrant an exam. % agreed that finding breast cancer early could lower the chance of dying of cancer. over % reported that mammograms were helpful in finding cancer. however, % believed that hav· ing a mammogram actually prevents breast cancer. % indicated that mammograms actually cause cancer and % reported that a woman should get a mammogram only if there is breast cancer in her family. conclusion: this survey indicates that current information about the importance of mammograms and clinical breast exams is reaching traditionally underserved women. yet there are still critical oppor· tunities to provide valuable education on breast health. this pilot study can serve as a tool for shaping future studies of health education messages for underserved populations. located in a yourh serv· ~ng agency m downtow~ ottawa, the clinic brings together community partners to provide primary medical care. and dent~i hygiene t? the street youths of ottawa aged - . the primary goal of the project is to provide accessible, coordinated, comprehensive health and dental care to vulnerable adolescents. these efforts respond to the pre-existing body of evidence suggesting that the principle barrier in accessing such care for these youths are feelings of intimidation and vulnerability in the face of a complex healthcare system. the bruyere fhn satellite clinic is located in the basement of a downtown drop-in and brings together a family medicine physician and her residents, a dental hygienist and her nd year students, a nurse practitioner, a chiropodist and public health nurses to provide primary care. the clinic has been extremely busy and well received by the youth. this workshop will demonstrate how five community organizations have come together to meet the needs of high risk youths in ottawa. this presentation will showcase the development of the clinic from its inception through its first year including reaction of the youths, partnerships and lessons learned. it will also focus on its sustainability without continued funding. we hope to have developed a model of service delivery that could be reproduced and sustained in other large cities with faculties of medicine. methods: non-randomized, mixed method design involving a process and impact evaluation. data collection-qualitative-a) semi structured interviews with providers & partners b)focus groups with youth quantitative a)electronic medical records for months records (budget, photos, project information). results: ) successfully built and opened a medicaudental clinic which will celebrate its year anniversary in august. ) over youths have been seen, and we have had over visits. conclusion: ) the clinic will continue to operate beyond the month project funding. ) the health of high risk youth in ottawa will continue to improve due to increased access to medical services. p - (a) health services -for the citizens of bangalore -past, present and future savita sathyagala, girish rao, thandavamurthy shetty, and subhash chandra bangalore city, the capital of karnataka with . million is the th most populous city in india; supporting % of the urban population of karnataka, it is considered as one of the fastest growing cities in india. known as the 'silicon valley of india', bangalore is nearly years old. bangalore city corporation (bmp), is a local self government and has the statutory commitment to provide to the citizens of bangalore: good roads, sanitation, street lighting, safe drinking water apart from other social obligations, cultural development and poverty alleviation activities. providing preventive and promotive heahh services is also a specific component. the objective of this study was to review the planning process with respect to health care services in the period since india independence; the specific research questions being what has been the strategies adopted by the city planners to address to the growing needs of the population amidst the background of the different strategies adopted by the country as a whole. three broad rime ranges have been considered for analysis: the s, s and the s. the salient results are: major area of focus has been on the maternal and child care with activities ranging from day-care to in-patient-care; though the number of institutions have grown from to the current day , their distribution has been far from satisfactory; obtaining support from the india population projects and major upgradarions have been undertaken in terms of infrastructure; over the years, in addition to the dispensaries of modern system of medicine, local traditional systems have also been initiated; the city has partnered with the healthy cities campaign with mixed success; disease surveillance, addressing the problems related to the emerging non-communicable diseases including mental health and road traffic injuries are still in its infancy. isolated attempts have been made to address the risks groups of elderly care and adolescent care. what stands out remarkably amongst the cities achievements is its ability to elicit participation from ngos, cbos and neighbourhood groups. however, the harnessing of this ability into the health sector cannot be said totally successful. the moot question in all the above observed development are: has the city rationally addressed it planning needs? the progress made so far can be considered as stuttered. the analysis and its presentation would identify the key posirive elements in the growth of banglore city and spell a framework for the new public health. introduction: anaemia associated with pregnancy is a major public health problem all over the world. different studies in different parts of india shown prevalence of anaemia between - %. anaemia remains a serious health problem in pregnancy despite of strong action taken by the government of india through national programmes. in the present study we identified th~ social beha~iors, responsible for low compliance of if a tablets consumption in pregnancy at community level and intervention was given with new modified behaviors on trial bases. . in vadodara urban. anganwadies out of were selected from the list by random sampling for tips (trials of improved practices) study. . . participants: pregnant women ( , intervention group+ , control. group) registered m the above anganwadies. study was conducted in to three phases: phase: . formative research and baseline survey (frbs). data was collected from all pregnant women to identify behaviors that are responsible for low compliance of ifa tablets. both qualitative and quantitative data were collected. haemoglobin was estimated of all pregnant women by haemo-cue. phase: . phase of tips. behaviors were identified both social & clinical for low compliance of ifa tablets consumption in pregnancy from frbs and against those, modified behaviors were proposed to pregnant women in the intervention group on trial bases by health education. trial period of weeks was given for trial of new behaviors to pregnant women in the interven· tion group. phase: . in this phase, feedbacks on behaviors tried or not tried were taken from pregnant women in intervention group. haemoglobin estimation was carried out again in all pregnant women. at the end of the study, messages were formulated on the bases of feedbacks from the pregnant women. results: all pregnant women in the intervention group had given positive feedback on new modified behaviors after intervention. mean haemoglobin concentration was higher in intervention group ( . ± . gm%) than control group ( . ± . gm%). ifa tablets compliance was improved in intervention group ( . %) than control group ( . %). conclusion: all pregnant women got benefits after trial of new modified behaviors in the intervention group. messages were formulated from the new modified behaviors, which can be used for longterm strategies for anaemia control in the community. introduction: in order to develop a comprehensive mch handbook for pregnant women and to assess its effect among them, a pilot study was carried out at the maternal and child health training institute (mchti), in dhaka, bangladesh. methods: from mchti a sample of pregnant women was selected and all subjects were women who were attending the first visit of their current pregnancy by using a random sampling method. of the subjects, women were given the mch handbook as case and women were not given the handbook as control. data on pre and post intervention of the handbook from the cases and controls were taken from data recording forms between the st of november and st of october, and data was analysed by using a multilevel analysis approach. this was a hospital-based action (case-control) research, and was applied in order to measure the outcome of pre and post intervention following the introduction of the handbook. data was used to assess the effects of utilisation of the handbook on women's knowledge, practice and utilisation of mch services. results: this study showed that the change of knowledge about antenatal care visits was . % among case mothers. knowledge of danger signs improved . %, breast feeding results . %, vaccination . % and family planning results improved . % among case. results showed some positive changes in women's attitudes among case mothers and study showed the change of practice in antenatal care visits was .u. % in the case. other notable changes were: change of practice in case mother's tetanus toxoid (ti), . %; and family planning . %. in addition, handbook assessment study indicated that most women brought the handbook on subsequent visits ( . %), the handbook was highly utilised (i.e. it was read by . %, filled-in by . %, and was used as a health education tool by . %). most women kept the handbook ( . %) and found it highly useful ( . %) with a high client satisfaction rate of . %. conclusion: pregnant women in the case group had higher knowledge, better practices, and higher utilisation of mch services than mothers in the control groups who used alternative health cards. if the handbook is developed with a focus on utilising a problem-oriented approach and involving the recomendations .of end~users, it is anticipated that the mch handbook will contribute significantly to ensuring the quahry of hfe of women and their children in bangladesh. after several meetmgs to identify the needs of the community, a faso clinic was opened at ncfs. health care professionals from smh joined with developmental and social service workers from ncfs to implement the faso diagnostic process and to provide culturally appropriate after-care. the clinic is unique in that its focus is the high risk urban aboriginal population of toronto. it accepts referrals of not only children and youth, but also of adults. lessons learned: response to the faso clinic at native child and family services has been overwhelming. aboriginal children with f asd are receiving timely diagnosis and interventions. aboriginal youth and adults who have been struggling with poveny, substance abuse, and homelessness are more willing to enter the ncfs centre for diagnosis and treatment. aboriginal infants prenatally exposed to alcohol born at st. michael's hospital or referred by other centres have access to the developmental programs located in both of the partnering agencies. the presentation will describe the clinic's development, and will detail the outcomes described, including interventions unique to the aboriginal culture. p - (c) seeds, soil, and stories: an exploration of community gardening in southeast toronto carolin taran, sarah wakefield, jennifer reynolds, and fiona yeudall introduction: community gardens are increasingly seen as a mechanism for improving nutrition and increasing food security in urban neighbourhoods, but the evidence available to support these claims is limited. in order to begin to address this gap in a way that is respectful of community knowledge and needs, the urban gardening research opportunities workgroup (ugrow) project explored the benefits and potential risks of community gardening in southeast toronto. the project used a community-based research (cbr) model to assess community gardens as a means of improving local health. the research process included interviews, focus groups, and participant observation (documented in field notes). we also directly engaged the community in the research process, through co-learning activities and community events which allowed participants to express their views and comment on emerging results. most of the research was conducted by a community-based research associate, herself a community gardener. key results were derived from these various sources through line-by-line coding of interview transcripts and field note review, an interactive and iterative process which involved both academic and community partners. results: these various data sources all suggest that enhanced health and access to fresh produce are important components of the gardening experience. they also highlight the central importance of empowering and community-building aspects of gardening to gardeners. community gardens were thought to play a role in developing friendships and social support, sharing food and other resources, appreciating cultural diversity, learning together, enhancing local place attachment and stewardship, and mobilizing to solve local problems (both inside and outside the garden). potential challenges to community gardens as a mechanism for communiry development include bureaucratic resistance to gardens, insecure land tenure and access, concerns about soil contamination, and a lack of awareness and under· standing by community members and decision-makers of all kinds. conclusion: the results highlight many health and broader social benefits experienced by commu· nity gardeners. they also point to the need for greater support for community gardening programs, par· ticularly ongoing the ongoing provision of resources and education programs to support gardens in their many roles. this research project is supported by the wellesley central health corporation and the centre for urban health initiatives, a cihr funded centre for research development hased at the univer· sity of toronto. p - (c) developing resiliency in children living in disadvantaged neighbourhoods sarah farrell, lorna weigand, and wayne hammond the traditional idea of targeting risk reduction by focusing on the development of eff~ctive coping strategies and educational programs has merit in light of the research reportmg_ that_ ~ lupl.e forms of problem behaviour consistently appear to be predicted by increasing exposure to den_uf able risk factors. as a result, many of the disadvantaged child and youth studies have focused on trymg to better _unde.r· stand the multiple risk factors that increase the likelihood of the development of at nsk behaviour m ch ldren/youth and the potential implications for prevention. this in turn has led t_o. the conclus on that community and health programs need to focus on risk reduction by helpm~ md v duals develop more effective coping strategies and a better understanding of the limitations of cenam pathologies, problematic v poster sessions coping behaviours and risk factors potentially inheren~ in high needs co~unities. ~owever, another ai:ea of research has proposed that preventative interventions should cons de~ .~rotecnve fa~ors alo~~ with reducing risk factors. as opposed to just emphasizing problems, vulnerab ht es, and deficits, a res liencybased perspective holds the belief that children, youth and their families. have strengths, reso~ce.s and the ability to cope with significant adversity in ways that are not only effective, but tend to result m mcreased ability to constructively respond to future adversity. with this in mind, a participatory research project sponsored by the united way of greater toronto was initiated to evaluate and determine the resiliency profiles of children - years (n = ) of recent immigrant families living in significantly disadvantaged communities in the toronto area. the presentation will provide an overview of the identified protective factors (both intrinsic and extrinsic) and resiliency profiles in an aggregated format as well as a summary of how the children and their parents interpreted and explained these strength-based results. as part of the focus groups, current community programs and services were examined by the participants as to what might be best practices for supporting the development and maintaining of resiliency in children, families and communities. it was proposed that the community model of assessing resiliency and protective factors as well as proposed best strength-based practice could serve as a guide for all in the community sector who provide services and programs to those in disadvantaged neighbourhoods. p - (c) naloxone by prescription in san francisco, ca and new york, ny emalie huriaux the harm reduction coalition's overdose project works to reduce the number of fatal overdoses to zero. located in new york, ny and san francisco, ca, the overdose project provides overdose education for social service providers, single-room occupancy hotel (sro) residents, and syringe exchange participants. the project also conducts an innovative naloxone prescription program, providing naloxone, an opiate antagonist traditionally administered by paramedics to temporarily reverse the effects of opiate overdose, to injection drug users (idus). we will describe how naloxone distribution became a reality in new york and san francisco, how the project works, and our results. the naloxone prescription program utilizes multiple models to reach idus, including sro-and street-based trainings, and office-based trainings at syringe exchange sites. trainings include information on overdose prevention, recognition, and response. a clinician conducts a medical intake with participants and provides them with pre-filled units of naloxone. in new york, funding was initially provided by tides foundation. new york city council provides current funding. new york department of mental health and hygiene provides program oversight. while the new york project was initiated in june , over half the trainings have been since march . in san francisco, california endowment, tides foundation, and san francisco department of public health (sfdph) provide funding. in addition, sfdph purchases naloxone and provides clinicians who conduct medical intakes with participants. trainings have been conducted since november . to date, nearly individuals have been trained and provided with naloxone. approximately of them have returned for refills and reported that they used naloxone to reverse an opiate-related overdose. limited episodes of adverse effects have been reported, including vomiting, seizure, and "loss of friendship." in new york, individuals have been trained and provided with naloxone. over overdose reversals have been reported. over half of the participants in new york have been trained in the south bronx, the area of new york with the highest rate of overdose fatalities. in san francisco, individuals have been trained and provided with naloxone. over overdose reversals have been reported. the majority of the participants in san francisco have been trained in the tenderloin, th street corridor, and mission, areas with the highest rates of overdose fatalities. the experience of the overdose project in both cities indicates that providing idus low-threshold access to naloxone and overdose information is a cost-effective, efficient, and safe intervention to prevent accidental death in this population. p - (c) successful strategies to regulate nuisance liquor stores using community mobilization, law enforcement, city council, merchants and researchers tahra goraya presenta~ion _will discuss ~uccessful environmental and public policy strategies employed in one southen: cahf?rmna commumty to remedy problems associated with nuisance liquor stores. participants ~ be given tools to understand the importance of utilizing various substance abuse prevention str~tegi~ to change local policies and the importance of involving various sectors in the community to a~_ st with and advocate for community-wide policy changes. recent policy successes from the commultles of pa~ad~na and altad~na will highlight the collaborative process by which the community mobilized resulnng m several ordmances, how local law enforcement was given more authority to monitor poster sessions v nonconforming liquor stores, how collaborative efforts with liquor store owners helped to remove high alcohol content alcohol products from their establishments and how a community-based organiz,uion worked with local legislators to introduce statewide legislation regarding the regulation of nuisance liquor outlets. p - (c) "dialogue on sex and life": a reliable health promotion tool among street-involved youth beth hayhoe and tracey methven introduction: street involved youth are a marginalized population that participate in extremely risky behaviours and have multiple health issues. unfortunately, because of previous abuses and negative experiences, they also have an extreme distrust of the adults who could help them. in , toronto public health granted funding to a non governmental, nor for profit drop-in centre for street youth aged - , to educate them about how to decrease rhe risk of acquiring hiv. since then the funding has been renewed yearly and the program has evolved as needed in order to target the maximum number of youth and provide them with vital information in a candid and enjoyable atmosphere. methods: using a retrospective analysis of the six years of data gathered from the "dialogue on sex and life" program, the researchers examined the number of youth involved, the kinds of things discussed, and the number of youth trained as peer leaders. also reviewed, was written feedback from the weekly logs, and anecdotal outcomes noted by the facilitators and other staff in the organization. results: over the five year period of this program, many of youth have participated in one hour sessions of candid discussion regarding a wide range of topics including sexual health, drug use, harm reduction, relationship issues, parenting, street culture, safety and life skills. many were new youth who had not participated in the program before and were often new to the street. some of the youth were given specific training regarding facilitation skills, sexual anatomy and physiology, birth control, sexually transmitted infections, hiv, substance use/abuse, harm reduction, relationships and discussion of their next steps/future plans following completion of the training. feedback has been overwhelmingly positive and stories of life changing decisions have been reported. conclusion: clearly, this program is a successful tool to reach street involved youth who may otherwise be wary of adults and their beliefs. based on data from the evaluation, recommendations have been made to public health to expand the funding and the training for peer leaders in order ro target between - new youth per year, increase the total numbers of youth reached and to increase the level of knowledge among the peer leaders. p - (c) access to identification and services jane kali replacing identification has become increasingly more complex as rhe government identification issuing offices introduce new requirements rhar create significant barriers for homeless people to replace their id. new forms of identification have also been introduced that art' not accessible to homekss peoplt-(e.g. the permanent resident card). ar rhe same time, many service providers continue to require identifi· cation ro access supports such as income, housing, food, health care, employment and employmt·nt training programs. street health, as well as a number of other agencies and community health centres, h, , been assisting with identification replacement for homeless peoplt· for a number of years. the rnrrt·nr challenges inherent within new replacement requirements, as well as the introduction of new forn ' of identification, have resulted in further barriers homeless people encounter when rrring to access t:ssential services. street health has been highlighting these issues to government identification issuing offices, as well as policy makers, in an effort to ensure rhar people who are homeless and marginalized have ac'ess to needed essential services. bandar is a somali word for •·a safe place." the bandar research project is the product of the regent park community health centre. the research looks ar the increasing number of somali and afri· can men in the homeless and precariously house population in the inner city core of down~own toronto. in the first phase of the pilot project, a needs assessment was conducted to dennfy barners and issues faced by rhe somali and other african men who are homeless and have add cr ns issues. th_e second phase of rhe research project was to identify long rerm resources and service delivery mechamsms that v poster sessions would enhance the abiity of this population to better access detox, treatment, and post treatment ser· vices. the final phase of the project was to facilitate the development of a conceptual model of seamless continual services and supports from the streets to detox to treatment to long term rehabilitation to housing. "between the pestle and mortar" -safe place. p - (c) successful methods for studying transient populations while improving public health beth hayhoe, ruth ewert, eileen mcmahon, and dan jang introduction: street youth are a group that do not regularly access healthcare because of their mis· trust of adults. when they do access health care, it is usually for issues severe enough for hospitalization or for episodic care in community clinics. health promotion and illness prevention is rarely a part of their thinking. thus, standard public health measures implemented in a more stable population do not work in this group. for example, pap tests, which have dearly been shown to decrease prevalence of cer· vical cancer, are rarely done and when they are, rarely followed up. methods to meet the health care needs and increase the health of this population are frequently being sought. methods: a drop-in centre for street youth in canada has participated in several studies investigating sexual health in both men and women. we required the sponsoring agencies to pay the youth for their rime, even though the testing they were undergoing was necessary according to public health stan· dards. we surmised that this would increase both initial participation and return. results: many results requiring intervention have been detected. given the transient nature of this population, return rates have been encouraging so far. conclusion: it seems evident that even a small incentive for this population increases participation in needed health examinations and studies. it is possible that matching the initial and follow-up incentives would increase the return rate even further. the fact that the youth were recruited on site, and not from any external advertising, indicates that studies done where youth trust the staff, are more likely to be successful. the presentation will share the results of the "empowering stroke prevention project" which incor· porated self-help mutual aids strategies as a health promotion methodology. the presentation will include project's theoretical basis, methodology, outcomes and evaluation results. self-help methodology has proven successful in consumer involvement and behaviour modification in "at risk," "marginalized" settings. self-help is a process of learning with and from each other which provides participants oppor· tunities for support in dealing with a problem, issue, condition or need. self-help groups are mechanisms for the participants to investigate existing solutions and discover alternatives, empowering themselves in this process. learning dynamic in self-help groups is similar to that of cooperative learning and peertraining, has proven successful, effective and efficient (haller et al, ) . the mutual support provided by participation in these groups is documented as contributory factor in the improved health of those involved. cognizant of the above theoretical basis, in the self-help resource centre initiated the "empowering stroke prevention project." the project was implemented after the input from health organizations, a scan of more than resources and an in-depth analysis of risk-factor-specific stroke prevention materials indicated the need for such a program. the project objectives were:• to develop a holistic and empowering health promotion model for stroke prevention that incorporates selfhelp and peer support strategies. • to develop educational materials that place modifiable risk factors and lifestyle information in a relevant context that validates project participants' life experiences and perspectives.• to educate members of at-risk communities about the modifiable risk factors associated with stroke, and promote healthy living. to achieve the above, a diverse group of community members were engaged as "co-editors" in the development of stroke prevention education materials which reflected and validated their life experiences. these community members received training to become lay health promoters (trained volunteer peer facilitators). in collaboration with local health organizations, these trained lay health promoters were then supported in organizing their own community-based stroke prevention activities. in addition, an educational booklet written in plain language, entitled healthy ways to prevent stroke: a guide for you, and a companion guide called healthy ways to pre· vent stroke: a facilitator's guide were produced. the presentation will include the results of a tw<>tiered evaluation of the program methodology, educational materials and the use of the materials beyond the life of the project. this poster presentation will focus on the development and structure of an innovative street outreach service that assists individuals who struggle mental illness/addictions and are experiencing homelessness. the mental health/outreach team at public health and community services (phcs) of hamilton, ontario assists individuals in reconnecting with health and social services. each worker brings to the ream his or her own skills-set, rendering it extremely effective at addressing the multidimensional and complex needs of clients. using a capacity building framework, each ream member is employed under a service contract between public health and community services and a local grassroots agency. there are public health nurses (phn), two of whom run a street health centre and one of canada's oldest and most successful needle exchange programs, mental health workers, housing specialists, a harm reduction worker, youth workers, and a united church minister, to name a few. a community advisory board, composed of consumers and professionals, advises the program quarterly. the program is featured on raising the roors 'shared learnings on homelessness' website at www.sharedlearnings.ca. through our poster presentation participants will learn how to create effective partnerships between government and grassroots agencies using a capacity building model that builds on existing programs. this study aims to assess the effects of broadcasting a series of documentary and drama videos, intended to provide information about the bc healthguide program in farsi, on the awareness about and the patterns of the service usage among farsi-speaking communities in the greater vancouver area. the major goals of the present study were twofold; ( ) to compare two methods of communications (direct vs. indirect messages) on the attitudes and perceptions of the viewers regarding the credibility of messengers and the relevance of the information provided in the videos, and ( ) to compare and contrast the impact of providing health information (i.e., the produced videos) via local tvs with the same materials when presented in group sessions (using vcr) on participants' attitudes and perceptions cowards the bc healrhguide services. results: through a telephone survey, farsi-speaking adults were interviewed in november and december . the preliminary findings show that % of the participants had seen the aired videos, from which, % watched at least one of the 'drama' clips, % watched only 'documentary' clip, and % watched both types of video. in addition, % of the respondents claimed that they were aware about the program before watching the aired videos, while % said they leaned about the services only after watching the videos. from this group, % said they called the bchg for their own or their "hildren's health problems in the past month. % also indicated that they would use the services in the future whenever it would be needed. % considered the videos as "very good" and thought they rnuld deliver relevant messages and % expressed their wish to increase the variety of subjects (produ\:e more videos) and increase the frequency of video dips. conclusion: the results of this study will assist public health specialists in bc who want to choose the best medium for disseminating information and apply communication interventions in multi\:ultural communities. introduction: many theorists and practitioners in community-based research (cbr) and knowledge transfer (kt) strongly advocate for involvement of potential users of research in the development of research projects, yet few examples of such involvement exist for urban workplace health interventions. we describe the process of developing a collaborative research program. methods: four different sets of stakeholders were identified as potential contributors to and users of the research: workplace health policy makers, employers, trade unions, and health and safety associations. representatives of these stakeholders formed an advisory committee which met quarterly. over the month research development period, an additional meetings were held between resc:ar~h~rs and stakeholders. in keeping with participant observation approaches, field notes of group and md v ~ ual meetings were kept by the two co-authors. emails and telephone calls were also documented. qu~h tative approaches to textual analysis were used, with particular attention paid to collaborattve v poster sessions relationships established (as per cbr), indicators of stakeholders' knowledge utilization (as per kt), and transformations of the proposed research (as per cbr). results: despite initial strong differences of opinion both among stakeho~ders .an~ between stakeholders and researchers, goodwill was noted among all involved. acts of rec~proc ty included mu.rual sharing of assessment tools, guidance on data utilization to stakeho~der orga~ zat ns, and suggestions on workplace recruitment to researchers. stakeholders demonstrated mcreases m concep~ual. un~erstand ing of workplace health e.g. they more commonly discussed more complex,. psychosocial md cators of organizational health. stakeholders made instrumental use of shared materials based on research e.g. adapting their consulting model to more sophisticated dat~ analysis. sta~ehol?~rs recogni_zed the strategic use of their alliance with researchers e.g., transformational leadership trainmg as a~ inducement to improve health and safety among small service franchises. stakeholders helped re-define the research questions, dramatically changed the method of recruitment from researcher cold call to stakeholderbased recruitment, and strongly influenced pilot research designs. owing a great deal to the elaborate joint development process, the four collaboratively developed pilot project submissions which were all successfully funded. conclusion: the intensive process of collaborative development of a research program among stakeholders and researchers was not a smooth process and was time consuming. nevertheless, the result of the collaborative process was a set of projects that were more responsive to stakeholder needs, more feasible for implementation, and more broadly applicable to relevant workplace health problems. introduction: environmental groups, municipal public health authorities and, increasingly, the general public are advocating for reductions in pesticide use in urban areas, primarily because of concern around potential adverse health impacts in vulnerable populations. however, limited evidence of the relative merits of different intervention strategies in different contexts exists. in a pilot research project, we sought to explore the options for evaluating pesticide reduction interventions across ontario municipalities. methods: the project team and a multi-stakeholder project advisory committee (pac), generated a list of potential key informants (kl) and an open ended interview guide. thirteen ki from municipal government, industry, health care, and environmental organizations completed face to face or telephone interviews lasting - minutes. in a parallel process, a workshop involving similar representatives and health researchers was held to discuss the role of pesticide exposure monitoring. minutes from pac meetings, field notes taken during ki interviews, and workshop proceedings were synthesized to generate potential evaluation methods and indicators. results: current evaluation activities were limited but all kls supported greater evaluation effons beginning with fuller indicator monitoring. indicators of education and outreach services were imponant for industry representatives changing applicator practices as well as most public health units and environmental organizations. lndictors based on bylaw enforcement were only applicable in the two cities with bylaws, though changing attitudes toward legal approaches were being assessed in many communities. the public health rapid risk factor surveillance system could use historical baseline data to assess changes in community behaviour through reported pesticide uses and practices, though it had limited penetration in immigrant communities not comfortable in english. pesticide sales (economic) data were only available in regional aggregates not useful for city specific change documentation. testing for watercourse or environmental contamination might be helpful, but it is sporadic and expensive. human exposure monitoring was fraught with ethical issues, floor effects from low levels of exposure, and prohibitive costs. clinical episodes of pesticide exposure reported to the regional poison centre (all ages) or the mother risk program (pregnant or breastfeeding women) are likely substantial underestimates that would be need to be supplemented with sentinel practice surveillance. focus on special clinical populations e.g., multiple chemical sensitivity would require additional data collection efforts . . conc~ons: broad support for evaluation and multiple indicators were proposed, though con-s~raints associate~ with access, coverage, sensitivity and feasibility were all raised, demonstrating the difficulty of evaluating such urban primary prevention initiatives. interventionists. an important aim of the youth monitor is to learn more about the health development of children and adolescents and the factors that can influence this development. special attention is paid to emo· tional and behavioural problems. the youth monitor identifies high-risk groups and factors that are associated with health problems. at various stages, the youth monitor chancrs the course of life of a child. the sources of informa· tion and methods of research are different for each age group. the results arc used to generate various kinds of repons: for children and young persons, parents, schools, neighbourhoods, boroughs and the municipality of rotterdam and its environs. any problems can be spotted early, at borough and neigh· bourhood level, based on the type of school or among the young persons and children themselves. together with schools, parents, youngsters and various organisations in the area, the municipal health service aims to really address these problems. on request, an overview is offered of potentially suitable interventions. the authors will present the philosophy, working method, preliminary effects and future developments of this instrument, which serves as the backbone for the rotterdam local youth policy. social workers to be leaders in response to aging urban populations: the practicum partnership program sarah sisco, alissa yarkony, and patricia volland "'" tliu:tion: across the us, . % of those over live in urban areas. these aging urban popu· lations, including the baby boomers, have already begun encounter a range of heahh and mental hcahh conditions. to compound these effects, health and social service delivery fluciuates in cities, whit:h arc increasingly diverse both in their recipients and their systems. common to other disciplines (medicine, nursing, psychology, etc.) the social work profession faces a shortage of workers who are well-equipped to navigate the many systems, services, and requisite care that this vast population requires. in the next two decades, it is projected that nearly , social workers will be required to provide suppon to our older urban populations. social workers must be prepared to be aging-savvy leaders in their field, whether they specialize in gerontology or work across the life span. mllhotu: in , a study conducted at the new york academy of medicine d<> :umcntcd the need for improved synchroniciry in two aspects of social work education, classroom instruction and the field experience. with suppon from the john a. hanford foundation, our team created a pilot proj~"t entitled the practicum pannership program (ppp) in master's level schools of social work, to improvt" aginr exposure in field and classroom content through use of the following: i) community-university partnrr· ships, ) increased, diverse student field rotations, ll infusion of competcn ."}'·drivm coursework, enhancement of field instructors' roles, and ) concentrated student recruitment. we conductt"d a prr· and post-test survey into students' knowledge, skills. and satisfaction. icarlja: surveys of over graduates and field inltnk."tors rcflected increased numlk-n of . rrm:y· univmity panncrships, as well as in students placed in aging agencin for field placements. there wa marked increase in student commitments to an aging specialization. onr year por.t·gradu:nion rcvealrd that % of those surveyed were gainfully employed, with % employed in the field of aginic. by com· bining curricular enhancement with real-world experiences the ppp instilled a broad exposurr for llu· dents who worked with aging populations in multiple urban settings. coltdtuion: increased exposure to a range of levels of practicr, including clinical, policy/ajvocaq, and community-based can potentially improve service delivery for older adulh who live in elfin, and potentially improve national policy. the hanford foundation has now elected to uppon cxpantion of the ppp to schools nationwide (urban and rural) to complement other domntic initiatives to cnhalk"c" holistic services for older adults across the aging spectrum. bodrgnn.ntl: we arc a team of rcscarcbcn and community panncn working tcj c(her to develop an in"itepth understanding of the mental health needs of homeless youth ~ages to ) (using qualiutivc and quantitative methods ' panicipatory rncarch methods). it is readily apparmt that '-neless youth cxpcricnce a range of mental health problems. for youth living on the street, menul illnew may be either a major risk factor for homelessnal or may frequently emcsge in response to coping with rhe multitudinous stressors associated with homclcslllcsi including exposure to violence, prasutt to pamaplte in v poster sessions survival sex and/or drug use. the most frequent psychiatric diagnoses amongst the homeless gencrally include: depression, anxiety and psychosis. . . . the ultimate ob ective of the pr~am of rei:e~ is to ~evelop a plan for intervention to meet the mental health needs of street youth. prior t_o pl~nnmg mtervenbons, .it is necessary to undertake a comprehensive assessment ~f mental health needs m this ~lnerable populanon. thus, the immediate objective of this research study is to undertake a comprehensive assessment of men· tal health needs. . . melbotlology: a mixed methodology triangulating qualitative, participatory acnon and quantitative methods will capture the data related to mental health needs of homeless youth. a purposive sample of approximately - subjecrs. ages to , is currently being ~ted ~participate from the commu.nity agencies covenant house, evergreen centre fo~ srrc;et youth, turning p? ?t and street ~ serv~. youth living on the street or in short -term residennal programs for a mmimum of month pnor to their participation; ages to and able to give infonned consent will be invited to participate in the study. o..tcomes: the expected outcome of this initial survey will be an increased understanding of mental health needs of street youth that will be used to develop effective interventions. it is anticipated that results from this study will contribute to the development of mental health policy, as well as future programs that are relevant to the mental health needs of street youth. note: it is anticipated that preliminary quantitative data ( subjects) and qualitative data will be available for the conference. the authors intend to present the identification of the research focus, the formation of our community-based team, relevance for policy, as well as preliminary results. p - (a) the need for developing a firm health policy for urban informal worken: the case of despite their critical role in producing food for urban in kenya, urban farmers have largely been ignored by government planners and policymakers. their activity is at best dismissed as peripheral eveo, inappropriate retention of peasant culture in cities and at worst illegal and often some-times criminal· ized. urban agriculture is also condemned for its presumed negative health impact. a myth that contin· ues despite proof to the contrary is that malarial mosquitoes breed in maize grown in east african towns. however, potential health risks are insignificant compared with the benefits of urban food production. recent studies too rightly do point to the commercial value of food produced in the urban area while underscoring the importance of urban farming as a survival strategy among the urban poor, especially women-headed households. since the millennium declaration, health has emerged as one of the most serious casualties consequent on the poverty, social exclusion, marginalisation and lack of sustain· able development in africa. hiv/aids epidemic poses an unprecedented challenge, while malaria, tuber· culosis, communicable diseases of childhood all add to the untenable burden. malnutrition underpins much ill-health and is linked to more than per cent of all childhood deaths. kenya's urban poor people ~ace ~ h~ge burde~ of preventable and treatable health problems, measured by any social and bi~ medical md cator, which not only cause unnecessary death and suffering, but also undermine econonuc development and damage the country's social fabric. the burden is in spite of the availability of suitable tools and re:c=hnology for prevention and treatment and is largely rooted in poverty and in weak healah •rstems. this pa~ therefore challenges development planners who perceive a dichotomy instead of con· tmuum between informal and formal urban wage earners in so far as access to health services is con· cemed. it i~ this gap that calls for a need to developing and building sustainable health systems among the urban mformal ~wellers. we recommend a focus on an urban health policy that can build and strengthen the capacity of urban dwellers to access health services that is cost-effective and sustainable. such ~ health poli<=>: must strive for equity for the urban poor, displaced or marginalized; mobilise and effect ~ely use sufficient sustainable resources in order to build secure health systems and services. special anenti_on. should ~ afforded hiv/aids in view of the unprecedented challenge that this epidemic poses to africa s economic and social development and to health services on the continent. methods: a review of the literature led us to construct three simple models and a composite model of exposure to traffic. the data were collected with the help of a daily diary of travel activities using a sample of cyclists who went to or come back from work or study. to calculate the distance, the length of journey, and the number of intersections crossed by a cyclist different geographic information systems (gis) were operated. statistical analysis was used to determine the significance between a measure of exposure on the one hand, and the sociodemographic characteristics of the panicipants or their geographic location on the other hand. restlltj: our results indicate that cyclists were significantly exposed to road accidents, no matter of where they live or what are their sociodemographic characteristics. we also stress the point that the fact of having been involved in a road accident was significantly related to the helmet use, but did not reduce the propensity of the cyclists to expose themselves to the road hazards. condlllion: the efforts of the various authorities as regards road safety should not be directed towards the reduction of the exposure of the vulnerable users, but rather towards the reduction of the dangers to which they could face. keywords: cyclist, daily diary of activities, measures of exposure to traffic, island of montreal. p - (a) intra urban disparities and environmental health: some salient features of nigerian residential neighbourhoods olumuyiwa akinbamijo intra urban disparities and environmental health: some salient features of nigerian residential neighbourhoods abstract urbanization panicularly in nigerian cities, ponends unprecedented crises of grave dimensions. from physical and demographic viewpoints, city growth rates are staggering coupled with gross inabilities to cope with the consequences. environmental and social ills associated with unguarded rapid urbanization characterize nigerian cities and threaten urban existence. this paper repons the findings of a recent study of the relationship between environmental health across inrraurban residential communities of akure, south west nigeria. it discuses the typical urbanization process of nigerian cities and its dynamic spatial-temporal characteristics. physical and socio-demographic attributes as well as the levels and effectiveness of urban infrastructural services are examined across the core residential districts and the elite residential layouts in the town. the incidence rate of cenain environmentally induced tropical diseases across residential neighborhoods and communes is examined. salient environmental variables that are germane to health procurement in the residential districts, incidence of diseases and diseases parasitology, diseases prevention and control were studied. field data were subjected to analysis ranging from the univariate and bivariate analysis. inferential statistics using the chi-square test were done to establish the truthfulness of the guiding hypothesis. given the above, the study affirms that there is strong independence in the studied communities, between the environment and incidence of diseases hence health of residents of the town. this assertion, tested statistically at the district levels revealed that residents of the core districts have very strong independence between the environment and incidences of diseases. the strength of this relationship however thins out towards the city peripheral districts. the study therefore concludes that since most of the city dwellers live in urban deprivation, urban health sensitive policies must be evolved. this is to cater for the urban dwellers who occupy fringe peripheral sites where the extension of facilities often times are illegally done. urban infrastructural facilities and services need be provided as a matter of public good for which there is no exclusive consumption or access even for the poorest of the urban poor. many suffer from low-self esteem, shame and guilt about their drug use. in addition, they often lack suppon or encounter opposition from their panners, family and friends in seeking treatment. these personal barriers are compounded by fragmented addiction, prenatal and social care services, inflexible intake systems and poor communication among sectors. the experience of accessing adequate care between services can be overwhelming and too demanding. the toronto centre for substance use in pregnancy (t-cup) is a unique program developed to minimize barriers by providing kone-stop" comprehensive healthcare. t-cup is a primary care based program located in the department of family medicine at st. joseph\'s health centre, a community teaching hospital in toronto. the interdisciplinary staff provides prenatal and addiction services, case management, as well as care of newborns affected by substance use. regular care plan meetings are held between t-cup, labour and delivery nurses and social workers in the y poster sessions maternity and child care program. t-cup also connects "'.omen with. inpatient treatment programs and community agencies such as breaking the cycle, an on-site counselmg group for pregnant substance users. · f · d d h ith method: retrospective chart review, qualitative patient ~ans action stu ~· an ea care provider surveys are used to determine outcomes. primary outcomes mclude changes m maternal su~tance use, psychosocial status and obstetrical complications (e.g. pre-rupture of membrane, pre-eclampsia, placen· ral abruption and hemorrhage). neonatal measures ~~nsisted of .bir~h pa_rame~ers, length of h~spital st.ay and complications (e.g. feral distress, meconium stammg, resuscitation, aund ce, hypoglycemia, seventy of withdrawal and treatment length). chart review consisted of all t-cup patients who met clinical cri· reria for alcohol or drug dependence and received prenatal and intra-partum care at st. joseph's from october to june . participants in the qualitative study included former and current t-cup patients. provider surveys were distributed on-site and to a local community hospital. raulb: preliminary evaluation has demonstrated positive results. treatment retention and satisfaction rates were high, maternal substance use was markedly reduced and neonatal outcomes have shown to be above those reported in literature. conclusion: this comprehensive, primary care model has shown to be optimal in the management of substance use in pregnancy and for improving neonatal outcomes. future research will focus on how this inexpensive program can be replicated in other health care settings. t-cup may prove to be the optimal model for providing care to pregnant substance users in canada. lntrod ction: cigarette smoking is one of the most serious health problems in taiwan. the prevalence of smoking in is . % in males . % in females aged years and older. although the government of taiwan passed a tobacco hazards control act in , it has not been strongly enforced in many places. therefore, community residents have often reported exposure of second hand smoke. the purpose of the study was to establish a device to build up more smoke-free environments in the city of tainan. methods: unique from traditional intervention studies, the study used a healthy city approach to help build up smoke-free environments. the major concept of the approach is to build up a healthy city platform, including organizing a steering committee, setting up policies and indicators, creating intersectoral collaboration, and increasing community participation. first, more than enthusiastic researchers, experts, governmental officers, city counselors and community leaders in tainan were invited in the healthy city committee. second, smoke-free policies, indicators for smoke-free environments, and mechanisms for inter-departmen· tal inspections were set up. third, community volunteers were recruited and trained for persuading related stakeholders. lastly, both penalties and rewards were used for help build up the environments. raults: aher two-year ( aher two-year ( - execution of the project, the results qualitatively showed that smoke-free environments in tainan were widely accepted and established, including smoke-free schools, smoke-free workpla~es, smoke-free households, smoke-free internet shops, and smoke-free restaurants. smoke~s were. effectively educated not to smoke in public places. community residents including adults and children m the smoke-free communities clearly understand the adverse effects of environmental tobacco smoke and actively participated anti-smoking activities. conclruions: healthy city platform is effective to conquer the barrier of limited anti-smoking rc:sources. nor. only can it enlar:ge community actions for anti-smoking campaigns, but also it can provide par_merships for collaboratjon. by establishing related policies and indicators the effects of smoke· free environments can be susta ·ned a d th · · · ' · n e progression can be monitored m a commuruty. these issues are used ~· oi::c it~ goals, weuha identifies issues that put people's health at risk. presently, team com~u:c: ran ee~tion !earns. (iats) that design integrative solutions ~tesj'°~ g om six to fifteen members. methods in order to establish wo-poster sessions v projects for weuha, the following approach was undertaken: i. a project-polling template was created and sent to all members of the alliance for their input. each member was asked to identify thdr top two population groups, and to suggest a project on which to focus over a - month period for each identified population. . there was a % response to the poll and the top three population groups were identified. data from the toronto community health profile database were utilized to contextualize the information supplied for these populations. a presentation was made to the steering committee and three population-based projects were selected, leaders identified and iats formed. three population-based projects: the population-based projects and health care issues identified are: newcomer prenatal uninsured women; this project will address the challenges faced by providers to a growing number of non-insured prenatal women seeking care. a service model where the barrier of "catchments" is removed to allow enhanced access and improved and co-ordinated service delivery will be pilot-tested. children/obesity/diab etes: using a health promotion model this team will focus on screening, intervention, and promoting healthy lifestyles (physical activity and nutrition) for families as well as for overweight and obese children. seniors health promotion and circle of discharge: this team will develop an early intervention model to assist seniors/family unit/caregivers in accessing information and receiving treatment/care in the community. the circle of discharge initiative will address ways of utilizing community supports to keep seniors in the community and minimize readmissions to acute care facilities. results/expected outcomes: coordinated and enhanced service delivery to identified populations, leading to improved access, improved quality of life, and health care for these targeted populations. introduction: basic human rights are often denied to high-risk populations and people living with hiv/aids. their rights to work and social security, health, privacy, non discrimination, liberty and freedom of movement, marriage and having a family have been compromised due to their sero-positive status and risk of being positive. the spread of hiv/aids has been accelerating due to the lack of general human rights among vulnerable groups. to formulate and implement effective responses needs dialogue and to prevent the epidemic to go underground barriers like stigma need to be overcome. objective: how to reduce the situation of stigma, discrimination and human rights violations experienced by people living with hiv/aids and those who are vulnerable to hiv/aids. methodology and findings: consultation meetings were strm.-rured around presentations, field visits, community meetings and group work to formulate recommendations on how govt and ngos/cbos should move forward based on objective. pakistan being a low prevalence country, the whole sense of compl;u:enc.:y that individuals are not subject to situations of vulnerable to hiv is the major threat to an explosion in th•· epidemic, therefore urgent measures are needed to integrate human rights issues from the very start of the response. the protection and promotion of human rights in an integral component of ;tll responses to the hiv/aids epidemic. it has been recognized that the response to hiv/aios must he multi sectoral and multi faceted, with each group contributing its particular expertise. for this to occur along with other knowlcdg<" more information is required in human rights abuses related to hiv/ aids in a particular scenario. the ~·on sultarion meetings on hiv/aids and human rights were an exemplary effort to achieve the same ohj<..:tivc. recommendations: the need for a comprehensive, integrated and a multi-sectoral appro;u.:h in addressing the issue of hiv/aids was highlighted. the need social, cultural and religious asp•·ct' to he: prominently addressed were identified. it was thought imperative measures even in low prevalence countries. education has a key role to play, there is a need for a code of ethics for media people and h<"alth care providers and violations should be closely monitored and follow up action taken. p - (c) how can community-based funding programs contribute to building community capacity and how can we measure this elusive goal? mary frances maclellan-wright, brenda cantin, mary jane buchanan, and tammy simpson community capacity building is recognized by the public health agency of canada (phac) as an important strategy for improving the overall health of communities by enabling communities to addre~s priority issues such as social and economic determinants of health. in / phac.:, alberta/nwf region's population health fund (phf) supported community-based projects to build community capacity on or across the determinants of health. specifically, this included creating accessible and sup· portive social and physical environments as well as creating tools and processes necessary for healthy policy development and implementation. the objective of this presentation is to highlight how the community capacity building tool, developed by phac ab/nwf region, can demonstrate gains in v poster sessions · · the course of a pror· ect and be used as a reflective tool for project planning and community capacity over . . . . i · a art of their reporting requirements, pro ect sites completed the community caparny eva uanon. s p . . th t i ii i'd d . building tool at the beginning and end of their ~ne-year prorect. e oo ~o ects va an reliable data in the context of community-based health prorects. developed through a vigorous ~nd collabora ve research process, the tool uses plain languag~ to expl~re nine key f~atures o~ commuruty cap~city with 't ch with a section for contextual information, of which also mdude a four-pomt raong ems, ea f fu d · scale. results show an increase in community capacity over the course o the nde prorects. pre and post aggregate data from the one-year projects measure~ statistic.ally si~n~ficant changes for of the scaled items. projects identified key areas of commumty capacity bmldmg that needed strengthemng, such as increasing participation, particularly among people with low incomes; engaging community members in identifying root causes; and linking with community groups. in completing the tool, projects examined root causes of the social and economic determinants of health, thereby exploring social justice issues related to the health of their community. results of the tool also served as a reflec· cion on the process of community capacity building; that is, how the project outcomes were achieved. projects also reported that the tool helped identify gaps and future directions, and was useful as a project planning, needs assessment and evaluation tool. community capacity building is a strategy that can be measured. the community capacity building tool provides a practical means to demonstrate gains in community capacity building. strengthening the elements of community capacity building through community-based funding can serve as building blocks for addressing other community issues. needs of marginalized crack users lorraine barnaby, victoria okazawa, barb panter, alan simpson, and bo yee thom background: the safer crack use coalition of toronto (scuc) was formed in in response to the growing concern for the health and well-being of marginalized crack users. a central concern was the alarm· ing hepatitis c rate ( %) amongst crack smokers and the lack of connection to prevention and health ser· vices. scuc is an innovative grassroots coalition comprised of front-line workers, crack users, researcher! and advocates. despite opposition and without funding, scuc has grown into the largest crack specific harm reduction coalition in canada and developed a nationally recognized sarer crack kit distribution program (involving community-based agencies that provide outreach to users). the success of our coalition derives from our dedication to the issue and from the involvement of those directly affected by crack use. setting: scuc's primary service region is greater toronto, a diverse, large urban centre. much ofour work is done in areas where homeless people, sex trade workers and drug users tend to congregate. recently, scuc has reached out to regional and national stakeholders to provide leadership and education. mandate: our mandate is to advocate for marginalized crack users and support the devdopmentof a com.p.rehensive harm reduction model that addresses the health and social needs facing crack users; and to fac htare the exchange of information between crack users, service providers, researchers, and policy developers across canada. owrview: the proposed workshop will provide participants with an overview of the devdopment of scuc, our current projects (including research, education, direct intervention and consultation), our challenge~ and s~ccesses and the role of community development and advocacy within the coalition. pre-senter~ will consist of community members who have personal crack use experience and front-line work· ers-, sc.uc conducted a community-based research project (toronto crack users perspectives, ) , in w~ich s focus groups with marginalized crack users across toronto were conducted. participants iden· t f ed health and social issues affecti h b · · · d " red . . ng t em, arrsers to needed services, personal strategies, an oue recommendations for improved services. presenters will share the methodology, results and recommen· datmns resulting from the research project. conc/usio": research, field observations and consultations with stakeholders have shown that cradck shmoke~s are at an. increased risk for sexually transmitted infections hiv/aids hepatitis c, tb an ot er serious health issues health · ff, · ' ' · · . · issues a ectmg crack users are due to high risk behavmurs, socio· economic factors, such as homeless d. · · · · d · . . ness, scrsmmat on, unemployment, violence incarceraoons, an soc a so at on, and a lack of comprehe · h i h · ' ns ve ea t and social services targeting crack users. · · sinct · s, owever arge remains a gross underesurnaoon. poster sessions v these are hospital-based reports and many known cases go unreported. however teh case, young age at first intercourse, inconsistent condom use and multiple partnersplace adolescents at high risks for a diverse array of stls, including hiv. about % of female nigerian secondary school students report initiating sexual intercourse before age years. % of nigerian female secondary school students report not using a condom the last time they had sexual intercourse. more than % of urban nigerian teens report inconsistent condom use. methods: adolescents were studied, ages to , from benin city in edo state. the models used were mother-daughter( ), mother -son( ), father -son ( ), and father-daughter( ). the effect of parent-child sexual communicationat baseline on child\'s report of sexual behavior, to months later were studied. greater amounts of sexual risk communication were asociated with markedly fewer episodes of unprotected sexual intercourse, reduced number of sexual partners and fewer episodes of unprotected sexual intercourse. results: this study proved that parents can exert more influence on the sexual knowledge attitudes and practise of their adolescent children through desired practises or rolemodeling, reiterating their values and appropriate monitoring of the adolescents\' behavior. they also stand to provide information about sexuality and various sexual topics. parental-child sexual communication has been found to be particularly influential and has been associated with later onset of sexual initiation among adolescents, less sexual activity, more responsible sexual attitudes including greater condom use, self efficacy and lower self -reported incidence of stis. conclusions: parents need to be trained to relate more effectively with their children/wards about issues related to sex and sexuality. family -based programs to reduce sexual risk-taking need to be developed. there is also the need to carry out cross-ethnicaland cross-cultural studies to identify how parent-child influences on adolescent sexual risk behavior may vary in different regions or countries, especially inthis era of the hiv pandemic. introduction: public health interventions to identify and eliminate health disparities require evidence-based policy and adequate model specification, which includes individuals within a socioecological context, and requires the integration of biosociomedical information. multiple public and private data sources need to be linked to apportion variation in health disparities ro individual risk factors, the health delivery system, and the geosocial environment. multilevel mapping of health disparities furthers the development of evidence-based interventions through the growth of the public health information network (phin-cdc) by linking clinical and population health data. clinical encounter data, administrative hospital data, population socioenvironmental data, and local health policy were examined in a three-level geocoded multilevel model to establish a tracking system for health disparities. nj has a long established political tradition of "home rule" based in elected municipal governments, which are responsible for the well-being of their populations. municipalities are contained within counties as defined by the us census, and health data are linked mostly at the municipality level. marika schwandt community organizers from the ontario coaliti~n again~t pove~, .along ":ith ~edical practitioners who have endorsed the campaign and have been mvolved m prescnbmg special diet needs for ow and odsp recipients, will discuss the raise the rates campaign. the organizati~n has used a special diet needs supplement as a political tool, meeting the urgent needs o.f .poor ~ople m toront~ while raising the issues of poverty as a primary determinant of health and nutrtnous diet as a preventative health mea· sure. health professionals carry the responsibility to ensure that they use all means available to them to improve the health of the individuals that they serve, and to prevent future disease and health conditions. most health practitioners know that those on social assistance are not able to afford nutritious foods or even sufficient amounts of food, but many are not aware of the extra dietary funds that are available aher consideration by a health practitioner. responsible nurse practitioners and physicians cannot, in good conscience, ignore the special needs diet supplement that is available to all recipients of welfare and disabiliry (ow and odsp). a number of toronto physicians have taken the position that all clients can justifiably benefit from vitamins, organic foods and high fiber diets as a preventative health measure. we know that income is one of the greatest predictors of poor health. the special needs diet is a health promotion intervention which will prevent numerous future health conditions, including chronic conditions such as cardiovascular disease, cancer, diabetes and osteoporosis. many communiry health centres and other providers have chosen to hold clinics to allow many patients to get signed up for the supplement at one time. initiated by the ontario coalition against poverty, these clinics have brought together commu· niry organizers, community health centers, health practitioners, and individuals, who believe that poverty is the primary determinant of poor health. we believe that rates must be increased to address the health problems of all people on social assistance, kids, elders, people with hiv/aids -everyone. even in the context of understaffing, it could be considered a priority activity that has potentially important health promotion benefits. many clients can be processed in a two hour clinic. most providers find it a very interesting, rewarding undertaking. in the ontario coalition for social justice found that a toronto family with two adults and two kids receives $ , . this is $ , below the poverty line. p - (c) the health of street youth compared to similar aged youth beth hayhoe and ruth ewert . lntrod~on: street youth are at an age normally associated with good health, but due to their risky ~hav ours and th~ conditions in which they live, they experience health conditions unlike their peer~ an more stable env r~nments. in addition, the majority of street youth have experienced significant physical, sexual ~nd em.ot onal abuse as younger children, directly impacting many of the choices they make around their physical and emotional health. we examined how different their health really is. . , methodl: using a retrospective analysis of the years of data gathered from yonge street mis· ~ • evergreen health centre, the top conditions of youth were examined and compared with national tren~s for similar aged youth. based on knowledge of the risk factors present in the group, rea· sons for the difference were examined. d' ~its: street youth experience more illness than other youth their age and their illnesses can bt . irect t ·~kc~ to the. conditions in which they live. long-term impacts of abus~ contribute to such signif· ~~nt t e t d~slpl air that youth may voluntarily engage in behaviours or lack of self care in the hope at t cir ve~ w perhaps come to a quicker end. concl non: although it has ion b k h th' dy clearly shows d'fi . h g ee~ no~n t at poverty negatively affects health, ~siu be used to make ; erence m t .e health of this particular marginalized population. the infonnanon can relates to th . ecommendatio.ns around public policy that affects children and youth, especially as it e r access to appropriate health care and follow up. p - (cl why do urban children · b gt . tarek hussain an adesh die: how to save our children? the traditional belief that urban child alid. a recent study (dhs d fr r~n are better off than rural children might be no longer v urban migrants are highata th om h c~untn~s i demonstrates that the child survival prospects of rural· er an t ose m their r j · · ·grants. in bangladesh, currently million ~r~ ~ gm and lower than those of urban non-idi million. health of the urban ~ p~e are hvmg m urban area and by the year , it would be so the popu at on s a key a eals that urban poor have the worse h h . concern. recent study on the urban poor rev ea t situation than the nation as a whole. this study shows that infant poster sessions v mortality among the urban poor as per thousand, which are above the rural and national level estimates. the mortality levels of the dhaka poor are well above those of the rest of the city's population but much of the difference in death rates is explained by the experience of children, especially infants. analyzing demographic surveillance data from a large zone of the city containing all sectors of the population, research showed that the one-fifth of the households with the least possessions exhibited u child mortality almost three times as high as that recorded by the rest of the population. why children die in bangladesh? because their parents are too poor to provide them with enough food, clean water and other basic needs to help them avoid infection and recover from illness. researchers believed that girls are more at risk than boys, as mothers regularly feed boys first. this reflects the different value placed on girls and boys, as well as resources which may not stretch far enough to provide for everyone. many studies show that housing conditions such as household construction materials and access to safe drinking water and hygienic toilet facilities are the most critical determinants of child survival in urban areas of developing countries. the present situation stressed on the need for renewed emphasis on maternal and child healthcare and child nutrition programs. mapping path for progress to save our children would need be done strategically. we have the policies on hand, we have the means, to change the world so that every child will survive and has the opportunity to develop himself fully as a healthy human being. we need the political will--courage and determination to make that a reality. p - (c) sherbourne health centre: innovation in healthcare for the transgendered community james read introduction: sherbourne health centre (shc), a primary health care centre located in downtown toronto, was established to address health service gaps in the local community. its mission is to reduce barriers to health by working with the people of its diverse urban communities to promote wellness and provide innovative primary health services. in addition to the local communities there are three populations of focus: the lesbian, gay, bisexual, transgendered and transexual communities (lgbtt); people who are homeless or underhoused; and newcomers to canada. shc is dedicated to providing health services in an interdisciplinary manner and its health providers include nurses, a nurse practitioner, mental health counsellors, health promoters, client-resource workers, and physicians. in january shc began offering medical care. among the challenges faced was how to provide responsive, respectful services to the trans community. providers had considerable expertise in the area of counselling and community work, but little in the area of hormone therapy -a key health service for those who want to transition from one gender to another. method: in preparing to offer community-based health care to the trans community it was clear that shc was being welcomed but also being watched with a critical eye. trans people have traditionally experienced significant barriers in accessing medical care. to respond to this challenge a working group of members of the trans community and health providers was created to develop an overall approach to care and specific protocols for hormone therapy. the group met over a one year period and their work culminated in the development of medical protocols for the provision of hormone therapy to trans individuals. results: shc is currently providing health care to registered clients who identify as trans individuals (march ) through primary care and mental health programs. in an audit of shc medical charts (january to september ) female-to-male (ftm) and male-to-female (mtf) clients were identified. less than half of the ftm group and just over two-thirds of the mtf group presented specifically for the provision of hormones. based on this chart audit and ongoing experience shc continues to update and refine these protocols to ensure delivery of quality care. conclusion: this program is an example of innovative community-based health delivery to a population who have traditionally faced barriers. shc services also include counselling, health promotion, outreach and education. p - (c) healthy cities for canadian women: a national consultation sandra kerr, kimberly walker, and gail lush on march , the national network on environment and women's health held a pan-canadian consultation to identify opportunities for health research, policy change, and action. this consultation also worked to facilitate information sharing and networking between canadian women working as urban planners, policy makers, researchers, and service workers on issues pertaining to the health of women living in canadian cities. methods: for this research project, participants included front-line service workers, policy workers, researchers, and advocates from coast to coast, including francophone women, women with disabilities, racialized women, and other marginalized groups. the following key areas were selected as topics for du.bnes i alto kading .:auk of end·sugr ieaal clileue ia singapore, accounting for more than so% of new can singapore (nkfs) to embark on a prevention program (pp) empo~r d ahc j u f dieir condition bttter, emphasizing education and disease sdf·managemen lkilla a. essennal camponenn of good glycaemic control. we sought explore the effects of a pecialijed edu.:a on pro· pun od glycacmic conuol, as indicated by, serum hba ic values budine serum hba ic values were determined before un<k-rgmng the education progr ;am, which couisted of comprehensive dietary advice, ideal weight goals, and improving lipid profiln. serum hbaic values were obtained ar , , months later to determine impact of the program. analy • wu done uling paired !·tests significant reduction in hba le levels from ro month• was observed in females, chinese race, older age group(> so yean). ohew-ibmi ~ .nwm , wai hip ratio> l),up to primary and above secondary level education and those having om urine iclt showed that increasing hbalc levels ( ) had increasing urmary protein ( .± ; . ±i ih so± ) and crearinine (s .s ± s ± ; ioi± s) levels fbg rnults showed that the management nf d abetn m the nkfs preven· tion programme is effec;rive. results also indicated har hba le leve have a linnr trend wnh unnary protein and creatinine which are imponant determinants of renal diseate tal family-focused cinical palbway promoce politivc outcollln for ua inner city canu allicy ipmai jerrnjm care llctivirits in preparation for an infanr'' dilchargr honlr, and art m endnl lo improve effi.:k'fl.:tn of c.are. lere i paucity of tttran:h, and inconsi trncy of rnulta on ht-•m!*- of f m ly·fc"-'uw d nm a: to determinr whrthrr implrmentation of family.focuted c:pt n ntnn.tt.tl unit w"n mg an inner city ;ommunity drcl't'aki leftarh of lf•y (i.osi and rromclll'i family uo•fkllon and rt. j nest for dikhargr. md odt: family-focuk"d cpi data wm coll«ted for all infant• horn btrwttn and wft"k• t"lal mi atr who wrtt . dm ed to the ntonatal unit lmgdl of -.y . n. . day'o p c o.osi ind pma . d•mr., ho.nr . t . n. . ± i. i wb, p < o.os) wett n« fiamly f.lfrt n the pre.(]' poup. ~ .fxtmon icofn for famihn wrre high. and families noctd thc:y wnr mott prepued to ah thrar t..lby "'-· thett was .a cosi uving of s , (cdn) per patient d teharpd home n the pmi-cp poap c.-pated the p"''lfoup· cortclaion· lmplrmrnr.rion of family·foanrd c:p. in a nrona . i umt tc"fyidi an nnn an com· muniry decre.ned length of'"'" mft with a high dcgrft of family uujamon, and wrre coll~nt at least % percent of the kathmandu population lives in slum like conditions with poor access to basic health services. in these disadvantaged areas, a large proportion of children do not receive treatment due to inaccessibility to medical services. in these areas, diarrhea, pneumonia, and measles, are the key determinants of infant mortality. protein energy malnutrition and vitamin a deficiency persists and communicable diseases are compounded by the emergence of diseases like hiv/aids. while the health challenges for disadvantaged populations in kathmandu are substantial, the city has also experienced various forms of innovative and effective community development health programs. for example, there are community primary health centers established by the kathmandu municipality to deliver essential health services to targeted communities. these centers not only provide equal access to health services to the people through an effective management system but also educate them hy organizing health related awareness programs. this program is considered one of the most effective urban health programs. the paper/presentation this paper will review large, innovative, and effective urhan health programs that are operating in kathmandu. most of these programs are currently run by international and national ngos a) early detection of emerging diseases in urban settings through syndromic surveillance: data pilot study kate bassil of community resources, and without adequate follow-up. in november shelter pr.oviders ~et with hospital social workers and ccac to strike a working group to address some of th~ issues by mcre.asing knowledge among hospital staff of issues surrounding homelessness, and to build a stro?g workmg relationship between both systems in hamilton. to date the hswg has conducted four w~lkmg to~ of downtown shelters for hospital staff and local politicians. recently the hswg launched its ·~ool.k t for staff working with patients who are homeless', which contains community resources and gu dehnes to help with effective discharge plans. a scpi proposal has been submitted to incre~se the capacity of the hswg to address education gaps and opportunities with both shelters and hospitals around homelessness and healthcare. the purpose of this poster presentation is to share hamilton's experience and learnings with communities who are experiencing similar issues. it will provide for intera~tion around shared experiences and a chance to network with practitioners across canada re: best practices. introduction and objectives: canadians view health as the biggest priority for the federal government, where health policies are often based on models that rely on abstract definitions of health that provide little assistance in the policy and analytical arena. the main objectives of this paper are to provide a functional definition of health, to create a didactic model for devising policies and determining forms of intervention, to aid health professionals and analysts to strategize and prioritize policy objectives via cost benefit analysis, and to prompt readers to view health in terms of capacity measures as opposed to status measures. this paper provides a different perspective on health, which can be applied to various applications of health such as strategies of aid and poverty reduction, and measuring the health of an individual/ community/country. this paper aims to discuss theoretical, conceptual, methodological, and applied implications associated with different health policies and strategies, which can be extended to urban communities. essentially, our paper touches on the following two main themes of this conference: •health status of disadvantaged populations; and •interventions to improve the health of urban communities.methodology: we initially surveyed other models on this topic, and extrapolated key aspects into our conceptual framework. we then devised a theoretical framework that parallels simple theories of physkal energy, where health is viewed in terms of personal/societal health capacities and effort components.after establishing a theoretical model, we constructed a graphical representation of our model using selfrated health status and life expectancy measures. ultimately, we formulated a new definition of health, and a rudimentary method of conducting cost benefit analysis on policy initiatives. we end the paper with an application example discussing the issues surrounding the introduction of a seniors program.results: this paper provides both a conceptual and theoretical model that outlines how one can go about conducting a cost-benefit analysis when implementing a program. it also devises a new definition and model for health barred on our concept of individual and societal capacities. by devising a definition for health that links with a conceptual and theoretical framework, strategies can be more logically constructed where the repercussions on the general population are minimized. equally important, our model also sets itself up nicely for future microsimulation modeling and analysis.implications: this research enhances one's ability to conduct community-based cost-benefit analysis, and acts as a pedagogical tool when identifying which strategies provide the best outcome. p - (a) good playgrounds are hard to find: parents' perceptions of neighbourhood parks patricia tucker, martin holmes, jennifer irwin, and jason gilliland introduction: neighbourhood opportunities, including public parks and physical activity or sports fields hav~ been. iden.tified as correlates to physical activity among youth. increasingly, physical activity among children s bemg acknowledged as a vital component of children's lives as it is a modifiable determinant of childh~d obesity. children's use of parks is mainly under the influence of parents; therefore, the purpose of this study was to assess parents' perspectives of city parks, using london ontario as a case study.m~~: this qualitative study targeted a heterogeneous sample of parents of children using local parks w thm london. parents with children using the parks were asked for minutes of their time and if willing, a s.hort interview was conducted. the interview guide asked parents for their opinion 'of city parks, particularly the one they were currently using. a sample size of parents is expected by the end of the summer.results: preliminary findings are identifying parents concern with the current jack of shade in local parks. most parents have identified this as a limitation of existing parks, and when asked what would make the parks better, parents agree that shade is vital. additionally, some parents are recognizing the v poster sessions focused discussions during the consultation: . women in _poverty . women with disability . immi· grant and racialized women . the built and _physica_l environment. . . . . r its· participants voiced the need for integration of the following issues withm the research and policy :::na; t) the intersectional nature of urban women's health i~sues wh~ch reflects the reality of women's complex lives ) the multisectional aspect of urban wo_m~n s health, ss~es, which reflects the diversity within women's lives ) the interse~roral _dynamics within _womens hves and urban health issues. these concepts span multiple sectors -mdudmg health, educat n, and economics -when leveraging community, research, and policy support, and engaging all levels of government.policy jmplicatiom: jn order to work towards health equity for women, plans for gender equity must be incorporated nationally and internationally within urban development initiatives: • reintroduce "women" and "gender" as distinct sectors for research, analysis, advocacy, and action. •integrate the multisectional, intersectional, and intersecroral aspects of women's lives within the framework of research and policy development, as well as in the development of action strategies. • develop a strategic framework to house the consultation priorities for future health research and policy development (for example, advocacy, relationship building, evidence-based policy-relevant research, priority initiatives}.note: research conducted by nnewh has been made possible through a financial contribution from health canada. the views expressed herein do not necessarily represent the views of health canada.p - (c) drugs, culture and disadvantaged populations leticia folgar and cecilia rado lntroducci n: a partir de un proyecto de reducci n de daiios en una comunidad urbana en situ· aci n de extrema vulnerahilidad surge la reflexion sobre el lugar prioritario de los elementos sociocuhurales en el acceso a los servicios de salud de diferentes colectivos urbanos. las "formas de hacer, pensar y sentir" orientan las acciones y delimitan las posibilidades que tienen los individuos de definir que algo es o no problema, asf como tambien los mecanismos de pedido de ayuda. el analisis permanenre del campo de "las culturas cotidianas" de los llamados "usuarios de drogas" aporta a la comprension de la complejidad del tema en sus escenarios reales, y colabora en los diseiios contextualizados de politicas y propuestas socio-sanitarias de intervenci n, tornandolas mas efectivas.mitodos: esta experiencia de investigaci n-acci n que utiliza el merodo emografico identifica elementos socio estructurales, patrones de consumo y profundiza en los elementos socio-simb icos que estructuran los discursos de los usuarios, caracterizandolos y diferenciandolos en tanto constitutivos de identidades socia les que condicionan la implementaci n del programas de reduccion de daiios.resultados: los resultados que presentaremos dan cuenta de las caracteristicas diferenciadas v relaciones particulares ~ntre los consumidores de drogas en este contexto espedfico. a partir de este e~tudio de caso se mtentara co ? enzar a responder preguntas que entendemos significativas a la hora de pensar intcrvcnciones a la med da de poblaciones que comparten ciertas caracteristicas socio-culturales. (cuales serian las .motivaciones para el cambio en estas comunidades?, cque elementos comunitarios nos ayudan a i:nnstnur dema~~a? • cque tenemos para aprender de las "soluciones" que ellos mismos encuenrran a los usos problemat cos? methods: our study was conducted by a team of two researchers at three different sites. the mapping consisted of filling in a chart of observable neighbourhood features such as graffiti, litter, and boarded housing, and the presence or absence of each feature was noted for each city block. qualitative observations were also recorded throughout the process. researchers analyzed the compiled quantitative and qualitative neighbourhood data and then analyzed the process of data collection itself.results: this study reveals the need for further research into the effects of physical environments on individual health and sense of well-being, and perception of investment in neighbourhoods. the process reveals that perceptions of health and safety are not easily quantified. we make specific recommendations about the mapping methodology including the importance of considering how factors such as researcher social location may impact the experience of neighbourhoods and how similar neighbourhood characteristics are experienced differently in various spaces. further, we discuss some of the practical considerations around the mapping exercise such as recording of findings, time of day, temperature, and researcher safety.conclusion: this study revealed the importance of exploring conceptions of health and well-being beyond basic physical wellness. it suggests the importance of considering one's environment and one's own perception of health, safety, and well-being in determining health. this conclusion suggests that attention needs to be paid to the connection between the workplace and the external environment it is situated in. the individual's workday experience does not start and stop at the front door of their workplace, but rather extends into the neighbourhood and environment around them. our procedural observations and recommendations will allow other researchers interested in the effect of urban environments on health to consider using this innovative methodology. introduction: responding ro protests against poor medical attention for sexually assaulted women and deplorable conviction rates for sex offenders, in the late s, the ontario government established what would become over hospital-based sexual assault care and treatment centres (sactcs) across the province. these centres, staffed around the clock with specially trained heath care providers, have become the centralized locations for the simultaneous health care treatment of and forensic evidence collection from sexually assaulted women for the purpose of facilitating positive social and legal outcomes. since the introduction of these centres, very little evaluative research has been conducted to determine the impact of this intervention. the purpose of our study was to investigate it from the perspectives of sexually assaulted women who have undergone forensic medical examinations at these centres.method: women were referred to our study by sactc coordinators across ontario. we developed an interview schedule composed of both closed and open-ended questions. twenty-two women were interviewed, face-to-face. these interviews were approximately one-to-two hours in length, and were transcribed verbatim. to date, have been analyzed for key themes.results: preliminary findings indicate that most women interviewed were canadian born ( 'yo), and ranged in age from to years. a substantial proportion self-identified as a visible minority ( 'x.). approximately half were single or never married ( %) and living with a spouse or family of origin ( %). most were either students or not employed ( %). two-thirds ( %) had completed high school and onethird ( %) was from a lower socio-economic stratum. almost two-fifths ( %) of women perceived the medical forensic examination as revictimizing citing, for example, the internal examination and having blood drawn. the other two-thirds ( %) indicated that it was an empowering experience, as it gave them a sense of control at a time when they described feeling otherwise powerless. most ( %) women stated that they had presented to a centre due to health care concerns and were very satisfied ( % ) with their experiences and interactions with staff. almost all ( %) women felt supported and understood.conclusions: this research has important implications for clinical practice and for appropriately addressing the needs of sexually assaulted women. what is apparent is that continued high-quality medical attention administered in the milieu of specialized hospital-based services is essential. at the same time, we would suggest that some forensic evidence collection procedures warrant reevaluation. the study will take an experiential, approach by chroruclmg the impa~ of the transition f m the streets to stabilization in a managed alcohol program through the techruque of narrative i~:uiry. in keeping with the shift in thinking in the mental health fie!~ ~his stu~y is based on a paradigm of recovery rather than one of pathology. the "inner views of part c pants hves as they portray their worlds, experiences and observations" will be presented (charm~z, , ~· ~)-"i?e p~ of the study is to: identify barriers to recovery. it will explore the exj?cnence of ~n~t zanon pnor to entry into the program; and following entry will: explore the meanmg ~nd defirutto~s of r~overy ~~d the impact of the new environment and highlight what supports were instrumental m movmg pan apants along the recovery paradigm.p -st (a) treating the "untreatable": the politics of public health in vancouver's inner city introdudion: this paper explores the everyday practices of therapeutic programs in the treadnent of hiv in vancouver's inner city. as anthropologists have shown elsewhere, therapeutic programs do not siinply treat physical ailments but they shape, regulate and manage social lives. in vancouver's inner city, there are few therapeutic options available for the treatment of -ilv. public health initiatives in the inner city have instead largely focused on prevention and harm reduction strategies such as needle exchange programs, safe injection sites, and safer-sex education. epidemiological reports suggest that less than a quarter of those living with hiv in the downtown eastside (dtes) are taking antiretroviral therapies raising critical questions regarding the therapeutic economy of antiretrovirals and rights to health care for the urban poor.methods: this paper is drawn from ethnographic fieldwork in vancouver's otes neighborhood focusing on therapeutic programs for hiv treatment among "hard-to-reach" populations. the research includes participant-observation at inner city health clinics specializing in the treatment of hiv; semi· structured interviews with hiv positive participants, health care professionals providing hiv treatment, and administraton working in the field of inner city public health; and, lastly, observation at public meetings and conferences surrounding hiv treatment.r.awlts: hiv prevention and treatment is a central concern in the lives of many residents living in the inner city -although it is just one of many health priorities afflicting the community. concerns about drug resistance, cost of antiretrovirals, and illicit drug use means that hiv therapy for most is characterized by the daily observation of their medicine ingestion at health clinics or pharmacies. daily observed treatment (dot) is increasingly being adopted as a strategy in the therapeutic management of "untreatable" populations. dot programs demand a particular type of subject -one who is "compliant" to the rules and regimes of public health. over emphasis on "risky practices," "chaotic lives," and "~dh~rence" preve~ts the public health system from meaningful engagement with the health of the marginalized who continue to suffer from multiple and serious health conditions and who continue to experience considerable disparities in health.~ the ~ffec~s of hiv in the inner city are compounded by poverty, laclc of safe and affordable houamg, vanous llegal underground economies increased rates of violence and outbreaks of ~~~·~ly tr~nsmitted infections, hepatitis, and tuberculosi: but this research suggests 'that public health uunauves aimed at reducing health disparities may be failing the most vulnerable and marginal of citiztl s. margaret malone ~ vi~lence that occurs in families and in intimate relationships is a significant urban, ~unity, and pu~hc health problem. it has major consequences and far-reaching effects for women, ~~--renho, you~ sen on, and families. violence also has significant effects for those who provide and ukllc w receive health care violence · · i · · . all lasses, · is a soc a act mvolvmg a senous abuse of power. it crosses : ' : ' ~ s;nden, ag~ ~ti~, cultures, sexualities, abilities, and religions. societal responseshali ra y oc:used on identificatton, crisis intervention and services for families and individuajs.promoten are only "-"--:-g to add h · ' · i in intimate relationshi with"-~"'.". ress t e issues of violence against women and vjoence lenga to consider i~ m families. in thi_s p~per, i analyze issues, propose strategies, and note c~· cannot be full -...l'-~ whork towards erad canng violence, while arguing that social justice and equity y -. ucvcu w en thett are people wh mnhod: critical social theory, an analysis that addresses culturally and ethnically diverse communities, together with a population health promotion perspective frame this analysis. social determinants of health are used to highlight the extent of the problem of violence and the social and health care costs.the ottawa charter is integrated to focus on strategies for developing personal skills, strengthening community action, creating supportive environments, devdoping healthy public policies, and re-orientating health and social services. attention is directed to approaches for working with individuals, families, groups, communities, populations, and society.ratdts: this analysis demonstrates that a comprehensive interdisciplinary, multisectoral, and multifaceted approach within an overall health promoting perspective helps to focus on the relevant issues, aitical analysis, and strategies required for action. it also illuminates a number of interacting, intersecting, and interconnecting factors related to violence. attention, which is often focused on individuals who are blamed for the problem of violence, is redirected to the expertise of non-health professionals and to community-based solutions. the challenge for health promoters working in the area of violence in families and in intimate relationships is to work to empower ourselves and the communities with whom we work to create health-promoting urban environments. social justice, equiry, and emancipatory possibilities are positioned in relation to recommendations for future community-based participatory research, pedagogical practices for health care practitioners, and policy development in relation to violence and urban health. the mid-main community health center, located in vancouver british columbia (bc), has a diverse patient base reflecting various cultures, languages, abilities, and socio-economic statuses. due to these differences, some mid-main patients experience greater digital divide barriers in accessing computers and reputable, government produced consumer health information (chi) websites, such as the bc healthguide and canadian health network. inequitable access is problematic because patient empowerment is the basis of many government produced chi websites. an internet terminal was introduced at mid-main in the summer of , as part of an action research project to attempt to bridge the digital divide and make government produced chi resources useful to a broad array of patients. multi-level interventions in co-operation with patients, with the clinic and eventually government ministries were envisioned to meet this goal. the idea of implementing multi-level interventions was adopted to counter the tendency in interactive design to implement a universal solution for the 'ideal' end-user [ ), which discounts diversity. to design and execute the interventions, various action-oriented and ethnographic methods were employed before and during the implementation of the internet terminal. upon the introduction of the internet terminal, participant observation and interviews were conducted using a motion capture software program to record a digital video and audio track of patients' internet sessions. this research provided insight into the spectrum of patients' capacities to use technology to fulfil their health information needs and become empowered. at the mid-main clinic it is noteworthy that the most significant intervention to enhance the usefulness of chi websites for patients appeared to be a human rather than a technological presence. as demonstrated in other ethnographic research of community internet access, technical support and capacity building is a significant component of empowerment ( ). the mid-main wired waiting room project indicates that medical practitioners, medical administrators, and human intermediaries remain integral to making chi websites useful to patients and their potential empowerment. ( ) over the past years the environmental yo~th alliance has been of~ering a.youth as~t. mappin~ program which trains young people in community research and evaluation. wh ~st the positive expenenc~ and relationships that have developed over this time attest to the success of this program, no evaluations has yet been undertaken to find out what works for t.he youth, what ~ould be changed, and what long term outcomes this approach offers for the youth, their local community, and urban governance. these topics will be shared and discussed to help other community disorganizing and uncials governments build better, youth-driven structures in the places they live.p - (a) the world trade center health registry: a unique resource for urban health researchers deborah walker, lorna thorpe, mark farfel, erin gregg, and robert brackbill introduction: the world trade center health registry (wfchr) was developed as a public health response to document and evaluate the long-term physical and mental health effects of the / disaster on a large, diverse population. over , people completed a wfchr enrollment baseline survey, creating the largest u.s. health registry. while studies have begun to characterize / bealth impacts, questions on long-term impacts remain that require additional studies involving carefully selected populations, long-term follow-up and appropriate physical exams and laboratory tests. wtchr provides an exposed population directory valuable for such studies with features that make ita unique resource: (a) a large diverse population of residents, school children/staff, people in lower man· hattan on / including occupants of damaged/destroyed buildings, and rescue/recovery/cleanup work· ers; (b) consent by % of enrollees to receive information about / -related health studies; (c) represenration of many groups not well-studied by other researchers; (c) email addresses of % of enrollees; (d) % of enrollees recruited from lists with denominator estimates; and (e) available com· parison data for nyc residents. wfchr strives to maintain up-to-date contact information for all enrollees, an interested pool of potential study participants. follow-up surveys are planned.methods: to promote the wtchr as a public health resource, guidelines for external researcher.; were developed and posted on (www.wtcregistry.org) which include a short application form, a twopage proposal and documentation of irb approval. proposals are limited to medical, public health, or other scientific research. researchers can request de-identified baseline data or have dohmh send information about their studies to selected wfchr enrollees via mail or email. applications are scored by the wtchr review committee, comprised of representatives from dohmh, the agency for toxic subst~nces and disease registry, and wtchr's scientific, community and labor advisory committees. a data file users manual will be available in early fall .~suits: three external applications have been approved in , including one &om a non-u.s. ~esearcher, all requesting information to be sent to selected wtchr enrollees. the one completed mail· mg~~ wtchr enrollee~ (o , wfc tower evacuees) generated a positive survey response rate. three additional researchers mtend to submit applications in . wfchr encourages collaborations between researchers and labor and community leaders.conclusion: studies involving wtchr enrollees will provide vital information about the long· term health consequences of / . wtchr-related research can inform communities, researcher.;, policy makers, health care providers and public health officials examining and reacting to and other disasters. t .,. dp'"f'osed: thi is presentation will discuss the findings of attitudes toward the repeat male client iden· ie as su e a and substance us'n p · · · · i · 'd . . - g. articipants will learn about some identified effective strategies or service prov ers to assist this group of i · f men are oft · d bl men. n emergency care settings, studies show that this group en viewe as pro emaric patient d i r for mental health p bl h h an are more ikely to be discharged without an assessmen !) ea rofr ems t. an or er, more cooperative patients (forster and wu · hickey er al., · r y resu ts om this study suggest th · · ' ' l · d tel' mining how best to h . d at negative amtudes towards patients, difficu nes e · as well pathways l_e_ p patientsblan ~ck of conrinuity of care influence pathways to mental health care. • uc\:ome pro emat c when p ti k · che system. m a ems present repeatedly and become "get stuc id methods: semi-structured intervie d . · (n= ), ed nurses (n= ) other ed ;s were con ucted with male ed patients (n= ), ed phys oans ' sta (n= ) and family physicians (n= ). patients also completed a poster sessions v diagnostic interview. interviews were tape-recorded, transcribed verbatim and managed using n . transcripts were coded using an iterative process and memos prepared capture emergent themes. ethics approval was obtained and all participants signed a detailed informed consent form.introduction: urban settings are particularly susceptible to the emergence and rapid spread of nt•w or rare diseases. the emergence of infectious diseases such as sars and increasing concerns over the next influenza pandemic has heightened interest in developing and using a surveillance systt·m which detects emerging public health problems early. syndromic surveillance systems, which use data b, scd on symptoms rather than disease, offer substantial potential for this by providing near-real-rime data which are linked to an automated warning system. in toronto, we are piloting syndromic data from the · emergency medical services (ems) database to examine how this information can be used on an ongoing basis for the early detection of syndromes including heat-related illness (hri), and influenza-like-illness (ill). this presentation will provide an outline of the planned desi_gn of this system and proposed evaluation. for one year, call codes which reflect heat-related illness or influenza-like-illness will be selected and searched for daily using software with a multifactorial algorithm. calls will he stratified by call code, extracted from the -ems database and transferred electronically to toronto public health. the data will be analyzed for clusters and aberrations from the expected with the realtime outbreak and disease surveillance (rods) system, a computer-based public health tool for the early detection of disease outbreaks. this -ems surveillance system will be assessed in terms of its specificity and sensitivity through comparisons with the well-established tracking systems already in place for hr! and ill. others sources of data including paramedic ambulance call reports of signs and . this study will introduce complementary data sources t~ the ed ch e~ complamt an~ o~~rthe-counter pharmacy sales syndromic surveillance data currently bemg evaluated m ~ther ontar~o cltles. . syndromic surveillance is a unique approach to proactive(~ dete~tmg early c.hangesm the health status of urban communities. the proposed study aims to provide evidence of differential effectiveness through investigating the use of -ems call data as a source of syndromic surveillance information for hr! and ili in toronto. introduction: there is strong evidence that primary care interventions, including screening, brief advi<:e, treatment referral and pharmacotherapy are effective in reducing morbidity and mortality caused by substance abuse. yet physicians are poor at intervening with substance users, in part because of lack of time, training and support. this study examines the hypothesis that shared care in addictions will result in decreased substance use and improved health status of patients, as well as increased use of primary care interventions by primary care practitioners (pcps). methods: the addiction medicine service (ams) at st. joseph's health centre's family medicine department is in the process of being transformed from its current structure as a traditional consult service into a shared care model called addiction shared care (asc). the program will have three components: education, office systems and clinical shared care. as opposed to a traditional consult service, the patient will be booked with both a primary care liaison worker (pcl) and addictions physician. patients referred from community physicians, the emergency department and inpatient medical and psychiatric wards will be recruited for the study as well as pcps from the surrounding community. the target sample size is - physicians and a similar number of patients. after initial consult, patient will be recruited into the study with their consent. the shared-case model underlines the interaction and collaboration with the patient's main pcp. asc will provide them with telephone consults, advice, support and re-assessment for their patients, as well as educational sessions and materials such as newsletters and informational kits.results: the impact of this transition on our patient care and on pcp's satisfaction with the asc model is currently being evaluated through a grant provided by the ministry of health & long term care. a retrospective chart review will be conducted using information on the patient's substance use, er/clinic visits, and their health/mood status. pcp satisfaction with the program will be measured through surveys and focus groups. our cost-effectiveness analysis will calculate the overall cost of the program per patient..conclusion: this low-cost service holds promise to serve as an optimal model and strategy to improve outcomes and reduce health care utilization in addict patients. the inner city public health project introduction the inner city public health project (icphp) was desi.gned to explore new an~ innovative ways to reach marginalized inner city populations that par-t c pate m high health-nsk beha~ ors. much of this population struggles with poverty, addictions, mental illness and homelessness, creatmg barriers to accessing health services and receiving follow-up. this pro ect was de~igned to evaluat~ .~e success of offering clinics in the community for testing and followup of communicable diseases uuhzmg an aboriginal outreach worker to build relationships with individuals and agencies. v n(demographics~ history ~f testi~g ~nd immunization and participation in various health-risk behaviors), records of tesnng and mmumzat ons, and mterviews with partner agency and project staff after one year.. results: t~e chr ~as i~strumental in building relationships with individuals and partner agencies ' .° the c~mmun_ ~ re_sultmg m req~ests for on-site outreach clinics from many of the agencies. the increase m parnc pat n, the chr mvolvement in the community, and the positive feedback from the agen? staff de~onstrated that.the project was successfully creating partnerships and becoming increasingly integrated m the community. data collected from clients at the initial visit indicated that the project was reaching its target populations and highlighted the unique health needs of clients, the large unmet need for health services and the barriers that exist to accessing those services. ~usion: the outreach clinics were successful at providing services to target populations of high health-nsk groups and had great support from the community agencies. the role of the chr was critical to the success of the project and proved the value of this category of health care worker in an urban aboriginal population. the unmet health needs of this disadvantaged population support the need for more dedicated resources with an emphasis on reducing access barriers. building a caring community old strathcona's whyte avenue, a district in edmonton, brought concern about increases in the population of panhandlers, street people and homeless persons to the attention of all levels of government. the issue was not only the problems of homelessness and related issues, but feelings of insecurity and disempowerment by the neighbourhood residents and businesses. their concerns were acknowledged, and civic support was offered, but it was up to the community itself to solve the problem. within a year of those meetings, an adult outreach worker program was created. the outreach worker, meets people in their own environments, including river valley camps. she provides wrap-around services rooted in harm reduction and health promotion principles. her relationship-based practice establishes the trust for helping clients with appropriate housing, physical and/or mental health issues, who have little or no income and family support to transition from homelessness. the program is an excellent example of collaboration that has been established with the businesses, community residents, community associations, churches, municiple services, and inner-city agencies such as boyle street community services. statistics are tracked using the canadian outcomes research institute homes database, and feedback from participants, including people who are street involved. this includes an annual general meeting for community and people who are homeless. the program's holistic approach to serving the homeless population has been integral, both in creating community awareness and equipping residents and businesses to effectively interact with people who are homeless. through this community development work, the outreach worker engages old strathcona in meeting the financial and material needs of the marginalized community. the success of this program has been surprising -the fact is that homeless people's lives are being changed; one person at a time and the community has been changed in how they view and treat those without homes. over two years, the program has successfully connected with approximately seventy-five individuals who call old strathcona home, but are homeless. thirty-six individuals are now in homes, while numerous others have been assisted in obtaining a healthier and safer lifestyles by becoming connected with other social/health agencies. the program highlights the roots of homelessness, barriers to change and requirements for success. it has been a thriving program and a model that works by showing how a caring community has rallied together to achieve prosperous outcomes. the spn has created models of tb service delivery to be used m part~ers~ p with phannaceunca compa-. · · -. t' ns cooperatives and health maintenance orgamzanons (hmos). for example, the mes, c v c orgamza , . · b tb d' · spn has established a system with pharmaceutical companies that help patients to uy me cmes at a special discounted rate. this scheme also allows patients to get a free one-_month's worth of~ dru_g supply if they purchase the first months of their regimen. the sy_s~e~s were ~es gned to be cm~pattble with existing policies for recording and documentation of the ph hppme national tuberculosis program (ntp). aside from that, stakeholders were also encouraged to be dots-enabled through the use of m~nual~ and on-line training courses. the spn initiative offers an alternative in easing the burden of tb sc:rv ce delivery from rhe public sector through the harnessing of existing private-sector (dsos). the learnmgs from the spn experience would benefit groups from other locales that _work no~ only on ~ but other health concerns as well. the spn experience showcases how well-coordinated private sector involvements help promote social justice in health delivery in urban communities.p - (c) young people in control; doing it safe. the safe sex comedy juan walter and pepijn v. empelen introduction: high prevalence of chlamydia and gonorrhoea have been reported among migrants youth in amsterdam, originating from the dutch antilles, suriname and sub-sahara africa. in addition, these groups also have high rates of teenage-pregnancy (stuart, ) and abortions (rademakers ), indicating unsafe sexual behaviour of these young people. young people (aged - ) from the so· called urban scene (young trendsetters in r&b/hip hop music and lifestyle) in amsterdam have been approached by the municipal health service (mhs) to collaborate on a safe sex project. their input was to use comedy as vehicle to get the message a cross. for the mhs this collaboration was a valuable opportunity to reach a hard-to-reach group.mdhods: first we conducted a need assessment by means of a online survey to assess basic knowledge and to similtaneously examine issues of interest concerning sex, sexuality, safer sex and the opposite sex. second, a small literature study was conducted about elements and essential conditions for succesful entertainment & education (e&e) (bouman ), with as most important condition to ensure that the message is realistic (buckingham & bragg, ) . third a program plan was developed aiming at enhancing the stl/hiv and sexuality knowledge of the young people and addressing communication and educational skills, by means of drama. subsequently a safe sex comedy show was developed, with as main topics: being in love, sexuality, empowerment, stigma, sti, hivand safer sex. the messages where carried by a mix of video presentation, stand up comedy, spoken word, rap and dance.results: there have been two safe sex comedy shows. the attendance was good; the group was divers' with an age range between and year, with the majority being younger than year. more women than men attended the show. the story lines were considered realistic and most of the audients recognised the situations displayed. eighty percent of the audients found the show entertaining and % found it edm:arional. from this %, one third considers the information as new. almost all respondents pointed our that they would promote this show to their friends.con.clusion: the s.h<_>w reached the hard-to-reach group of young people out of the urban scene and was cons d_ered entert~mmg, educational and realistic. in addition, the program was able in addressing important issues, and impacted on the percieved personal risk of acquiring an sti when not using condoms, as well as on basic knowledge about stl's. introduction: modernity has contributed mightily to the marginality of adults who live with mental illnesses and the subsequent denial of opportunities to them. limited access to social, vocational, educational, and residential opportunities exacerbates their disenfranchisement, strengthening the stigma that has been associated with mental illness in western society, and resulting in the denial of their basic human rights and their exclusion from active participation in civil society. the clubhouse approach tn recovery has led to the reduction of both marginality and stigma in every locale in which it has been implemented judiciously. its elucidation via the prism of social justice principles will lead to a deeper appreciation of its efficacy and relevance to an array of settings. methods: a review of the literature on social justice and mental health was conducted to determine core principles and relationships between the concepts. in particular, fondacaro and weinberg's ( ) conceptualization of social justice in community psychology suggests the desirability of the clubhouse approach in community mental health practice. a review of clubhouse philosophy and practice has led to the inescapable conclusion that there is a strong connection between clubhouse philosophy-which represents a unique approach co recovery--and social justice principles. placing this highly effective model of community mental health practice within the context of these principles is long overdue. via textual analysis, we will glean the principles of social justice inherent in the rich trove of clubhouse literature, particularly the international standards of clubhouse development.results: fondacarao and weinberg highlight three primary social justice themes within their community psychology framework: prevention and health promotion; empowerment, and a critical pnsp<"<·tive. utilizing the prescriptive principles that inform every detail of clubhouse development and th<" movement toward recovery for individuals at a fully-realized clubhouse, this presentation asserts that both clubhouse philosophy and practice embody these social justice themes, promote human rights, and empower clubhouse members, individuals who live with mental illnesses, to achieve a level of wdl-heing and productivity previously unimagined.conclusion: a social justice framework is critical to and enhances an understanding of the clubhouse model. this model creates inclusive communities that lead to opportunities for full partic pil!ion civil society of a previously marginalized group. the implication is that clubhouses that an· based on the international standards for clubhouse programs offer an effective intervention strategy to guarantee the human rights of a sizable, worthy, and earnest group of citizens. to a drastic increase in school enrollment from . million in to . million in .s. however, while gross enrollment rates increased to °/., in the whole country after the introduction of fpe, it remained conspicuously low at % in the capital city, nairobi. nairobi city's enrollment rate is lower .than thatof all regions in the country except the nomadic north-eastern province. !h.e.d sadvantage of children bas_ed in the capital city was also noted in uganda after the introduction of fpe m the late s_-many_ education experts in kenya attribute the city's poor performance to the high propornon of children hvmg m slums, which are grossly underserved as far as social services are concerned. this paper ~xammes the impact of fpe and explores reasons for poor enrollment in informal settlements m na rob city. methods: the study utilizes quantitative and qualitative schooling data from the longitudinal health and demographic study being implemented by the african population and health research center in two informal settlements in nairobi. descriptive statistics are used to depict trends in enrollment rates for children aged - years in slum settlements for the period - . results: the results show that school enrollment has surprisingly steadily declined for children aged - while it increased marginally for those aged - . the number of new enrollments (among those aged years) did not change much between and while it declined consistently among those aged - since . these results show that the underlying reasons for poor school attendance in poverty-stricken populations go far beyond the lack of school fees. indeed, the results show that lack of finances (for uniform, transportation, and scholastic materials) has continued to be a key barrier to schooling for many children in slums. furthermore, slum children have not benefited from fpe because they mostly attend informal schools since they do not have access to government schools where the policy is being implemented.conclusion: the results show the need for equity considerations in the design and implementation of the fpe program in kenya. without paying particular attention to the schooling needs of the urban poor children, the millennium development goal aimed at achieving universal primary education will remain but a pipe dream for the rapidly increasing number of children living in poor urban neighborhoods.ps- (c) programing for hiv/aids in the urban workplace: issues and insights joseph kamoga hiv/aids has had a major effect on the workforce. according to !lo million persons who are engaged in some form of production are affectefd by hiv/aids. the working class mises out on programs that take place in communities, yet in a number of jobs, there are high risks to hiv infection. working persons sopend much of their active life time in workplaces and that is where they start getting involved in risky behaviour putting entire families at risk. and when they are infected with hiv, working people face high levels of seclusion, stigmatisation and some miss out on benefits especially in countries where there are no strong workplace programs. adressing hiv/aids in the workplace is key for sucessfull responses. this paper presents a case for workplace programing; the needs, issues and recommendations especially for urban places in developing countries where the private sector workers face major challenges. key: cord- -lt is is authors: preston, nicholas d.; daszak, peter; colwell, rita r. title: the human environment interface: applying ecosystem concepts to health date: - - journal: one health: the human-animal-environment interfaces in emerging infectious diseases doi: . / _ _ sha: doc_id: cord_uid: lt is is one health approaches have tended to focus on closer collaboration among veterinarians and medical professionals, but remain unclear about how ecological approaches could be applied or how they might benefit public health and disease control. in this chapter, we review ecological concepts, and discuss their relevance to health, with an emphasis on emerging infectious diseases (eids). despite the fact that most eids originate in wildlife, few studies account for the population, community, or ecosystem ecology of the host, reservoir, or vector. the dimensions of ecological approaches to public health that we propose in this chapter are, in essence, networks of population dynamics, community structure, and ecosystem matrices incorporating concepts of complexity, resilience, and biogeochemical processes. definitions of one health have varied among different authors and institutions, but a defining central tenet is that a one health approach brings a holistic understanding of health. this broader view includes human medicine, veterinary medicine, and an understanding of the ecological context of health (which we call 'ecohealth'). to date, one health approaches have tended to focus on closer collaboration among veterinarians and medical professionals, but remain unclear about how ecological approaches could be applied or how they might benefit public health and disease control. in this chapter, we review ecological concepts, and discuss their relevance to health, with an emphasis on infectious diseases, notably emerging infectious diseases (eids). nearly two-thirds of eids are zoonotic, and a majority of those ( %) originate in wildlife (anderson et al. ; cleaveland et al. ; daszak ) . diseases are considered 'emerging' if they are identified as occurring in a new geographic area, expanding their incidence rapidly, displaying novel genetic code, or moving into humans for the first time. the most important are pandemics, those that become established in humans and spread internationally. pandemics tend to be zoonotic, foodborne, or antimicrobial resistant pathogens, and their emergence and spread is overwhelmingly a result of changes in human demography (e.g. travel, population growth), behavior (e.g. drug use), economic activity (e.g. agricultural intensification), or anthropogenic changes to the environment (e.g. land-use change, climate change) (weiss and mcmichael ; jones et al. ) . the interactions among these underlying drivers and the dynamics of pathogens in wildlife, livestock, and people are a key focus of studies of the ecology of infectious diseases. ecology emerged from natural history and rose to prominence as a scientific discipline in the late nineteenth century as the 'study of the interactions of organisms with their environment' (haeckel ) . while originally a descriptive science, the theories of adaptation, evolution, and speciation rapidly became central to the field, and led to increasingly analytical approaches (lawton ) . over the past few decades, ecologists have analyzed data from field observations, laboratory studies, and large-scale field experiments to describe the structure and dynamics of populations, their interactions within communities, and the complexity of ecosystems. in this chapter, we build on the work of wilcox and jessop ( ) and last ( ) , adding an ecosystem network perspective to describe how ecological approaches can be focused on infectious diseases. we focus on three components: population, community, and ecosystem ecology. population ecology is the study of the population dynamics of a species with relevant metrics of density, natality, mortality, immigration, and emigration (hall ; murray ) . population dynamics are generated through competition, predation, parasitism, and the distribution of species. community ecology describes the clustering of populations of species into communities and the processes that dictate composition and diversity. pertinent community metrics are similarity, continuity, species, and genetic diversity. ecosystem ecology is the study of biotic and abiotic components of ecological systems, their biophysical interactions, and the flow of energy and materials (lindeman ; odum ; cook ) . the metrics for ecosystems include state, rates, and productivity. ecosystems provide the framework for organization of species and resource compartments, and modulate rates and dynamics of functions, processes, and services. in modern ecological approaches, a network perspective can be used to describe interactions among ecosystem components, with populations referred to as nodes, links between nodes in a community as edges, and the overall environment and abiotic components as an ecosystem matrix (fig. ) . this framework complements a shift in ecosystem thinking from structures and hierarchies, to networks and webs. while the concepts in this chapter are presented in the context of wildlife and emerging infectious diseases, they are generalizable to diverse ecosystem interactions. traditional views of ecosystems were focused on the concept of directional succession, whereby ecosystems developed along a predictable pathway to a climax system (e.g. mature deciduous forest) (clements ; gleason ) . in reality, ecosystems are dynamic and complex aggregations of communities continually adapting to internal and external influences. rarely are they stable or at fig. diagram illustrating the ecosystem components described in the text: a node is a population of organisms; edges are links between nodes in a community; and the overall environment including abiotic components is the ecosystem matrix. nodes are structured vertically into trophic levels and horizontally along an environmental gradient equilibrium, as described by static representations of food chains, trophic guilds, and species dominance. moreover, they demonstrate non-equilibrium dynamics in a mosaic of patches shifting among stable states when disturbed. the complex structure of ecosystems has long frustrated efforts to forecast and predict their behavior, yielding models of resilience, complexity, and chaos. ecosystems: abundance, structure, and flow historically, public health has focused on the dynamics and structure of human populations-only a single node within the context of global ecosystems. holistically, human health can best be considered in the context of other organisms within a network of populations, communities, and ecosystem interactions. infectious diseases within a one health context require an additional dimension, namely the natural environment as the habitat of the disease agents themselves, examples of which include water borne diseases. population ecology focuses on the dynamics of an individual species in a defined area, where the malthusian growth model is a central theory. however, wildlife populations are not static, nor is their growth linear. moreover, they display complex cycles and populations evolve from interactions, including competition, predation, herbivory, and mutualism, while demonstrating stochastic dynamics and lagged responses to disturbance. because knowledge of wildlife populations still is incomplete, there are many species for which historic data are lacking or routine monitoring not yet possible. furthermore, coverage varies across geographic regions, taxonomic groups, size, abundance, and economic or social values. despite the fact that most eids originate in wildlife, few studies account for the population dynamics of the host, reservoir, or vector, in contrast to studies of human populations and demographics. this uncertainty concerning wildlife health presents a threat both to domestic animals and human populations. at a minimum, those infectious disease agents closely linked to human health should be identified and subjected to intense study, e.g., those that incubate and spread disease or provide ecological services such as disease regulation and/or vaccine discovery. identifying these key species helps set priorities for routine surveillance, as well as uncovering as yet unknown species that present a threat or cure. fluctuations in host and vector abundance engender a variable risk distribution for disease transmission. some species are unique in their proximity to human physiology (e.g. primates and wild pigs) or in their expansive ranges (e.g. birds and bats), posing unique threat as integrators, spreaders, and laboratories for recombination and mutation of disease pathogens (daszak ) . wildlife population ecology can be employed to improve global health models, but within limitation. populations are difficult to define and species-based definitions are generally inadequate. those that are naturally or artificially isolated often exhibit distinct behaviors and present differential risks (levins ). populations are a continuum, where factors such as age, sex, and size can influence risk of disease transmission, especially where distribution of the agent is not uniform. thus, it is simplistic at best to consider population dynamics in isolation from the community structure and ecosystem matrix. community ecology describes an assemblage of nodes and their interactions, or edges. the contributions of individual populations can be characterized by employing network metrics, an example of which would be a high degree of connectivity that identifies critical, keystone nodes influencing the structure of the system. it should be noted that communities can demonstrate both equilibrium and non-equilibrium dynamics. characterizing biodiversity is fundamental to community ecology. it is also one of the more widely reported and popular concepts. biodiversity varies across spatial scales and describes both intraspecific or genetic diversity of a node, as well as diversity of nodes described in terms of richness, abundance, and evenness (bisby ; jost ; whittaker ) . food webs represent a central concept in ecology, being employed to model community structure as complex hierarchies of nodes (lindeman ; elton ; forbes ; hairston et al. ). inter-node interactions (edges) among consumers and resources form the backbone of food-web networks and the nodes can be structured into trophic levels, or functional groups, such as top predators (borrvall and ebenman ; finke and denno ) , mesopredators (elmhagen and rushton ), herbivores, and primary producers. edges are generally unidirectional, but can flip during the life history of an organism when lower trophic levels prey on juveniles of higher trophic levels. single trophic food webs are the simplest (tilman ), but few real-world examples exhibit those dynamics, with multi-trophic perspectives more realistic, albeit complex (cohen ; deangelis ; polis and winemiller ) . predator-prey relationships are dominant in representations of the structure of trophic hierarchies, along with the influences of co-evolution, mutualism, autotrophy, herbivory, competition, genetics, and speciation. food webs are structured from top and bottom. top-down control of food webs can occur via predation and resource consumption by consumers, influencing community size structure. at the same time, bottom-up mechanisms operate via abundance, availability, and edibility of primary producers (autotrophs) and secondary producers (herbivores). structural dynamics of a system, i.e., arrangement of nodes and edges, can influence the magnitude and variability of community response to disturbance. endogenous (internal) pressure from one node can reorganize the entire system. food webs are often portrayed with linear connections among trophic levels; however, responses to exogenous (external) disturbance can expose complex nonlinear dynamics and feedback loops. unlike characterizations such as a balance of nature or tree of life, it is apparent from food-web manipulations that ecological networks are complex systems encompassing hierarchies, webs, nested systems, cycles, and flows (carpenter and kitchell ; scheffer and carpenter ) . when ecology is incorporated into public health endeavors, the scope is frequently limited to distribution and abundance of individual nodes. studying the population dynamics of disease hosts and vectors clearly is important if zoonotic disease emergence is to be understood, but populations need to be studied in the context of edges defining their interactions with other nodes. indeed, a community approach to disease emergence can reveal important nodes and interactions that differ from those identified in population analyses. for example, some nodes, such as keystone species, may be disproportionally important to the system due to strong connectivity or high centrality. superspreaders are highly connected and rapidly disseminate disease through a network. identifying and monitoring the keystone species, superspreaders, and nodes that regulate host and vector abundance is important in disease prevention and control. trophic cascades regulate host abundance when changes at one trophic level cascade through the food web. for example, when a predator population collapses, regulation of the disease is reduced if the disease host or vector is thereby released from control by predation. removing predators directly relieves pressure on prey abundance and may also alter physiological stress, behavior (bakker et al. ) , and morphology (werner and peacor ) of their prey. clearly, both host and predator require monitoring in such circumstances. inter-species competition affects abundance, evolution, diversity, and pathogenicity of a disease agent. these processes can be tightly coupled to their pathogen hosts and, in turn, the community dynamics of the system. hence, the invasion of an exotic species, triggered by wildlife trade, transportation, or climate change for example, could cause food webs to reorganize thereby altering the probability of disease emergence. on one hand, the introduction of a species like the tiger mosquito (aedes albopictus), which is an aggressive disease vector, can alter the conditional (binary) probability of contracting certain vector-borne diseases. on the other hand, invasions by suboptimal hosts can 'dilute' disease risk. invasions can also introduce boom and bust dynamics, destabilizing systems and tipping native populations into irreversible alternate states. invasive species also diverge genetically from their original populations through isolation and founder effects, contributing to ''waves'' of disease occurrence. spatiotemporal variance in food webs is particularly acute for migratory populations, where resource consumption changes with habitat and the effect on nodes in one system can be transferred to another. in effect, migration provides a unique opportunity for populations and communities to exchange pathogens. in these scenarios, mapping distributed food webs could help identify pathways for disease transmission. food web and community network analyses introduce a high degree of complexity to mathematical and statistical models of systems. furthermore, it is difficult to determine accurately the trophic position of individual nodes in food web models. while advances in stable isotope analysis, fatty acids, and ecological stoichiometry help determine trophic position relative to other nodes in the community, as well as composition of diet; isotopic measurements often have location-specific limitations, whereby values are relative to local autotrophic production in the system as influenced by external subsidies. thus, it is difficult to draw meaningful comparisons among food webs. what is required is a method that generalizes models and captures topological position and functional importance of networks without a food web-specific bias (olff et al. ). by using food-web manipulations, it has been possible to demonstrate biogeochemical processes play an important role in structuring communities (carpenter and kitchell ; scheffer and carpenter ) . so, although community ecology considers both nodes and the edges that connect them, these systems must ultimately be studied in the context of their environment or ecosystem matrix. ecosystem ecology encompasses biophysical mechanisms regulating ecosystem metabolism across both biotic and abiotic compartments, this includes ecological function, physiological processes, populations and communities, resource availability, nutrient cycling, and connections among systems. the connections, flows, and cycles affecting the life history of an organism are highlighted, including materials of composition and their life cycle. traversing networks that incorporate abiotic pathways may help map these connections, a useful example of which is the carbon cycle, with biotic and abiotic compartments through which carbon can flow, sequester, or transform. the ecosystem matrix is a spatiotemporal mosaic that provides background structure for ecosystem networks. it is a complex system with unpredictable dynamics, including bidirectional relationships among organisms that extract, modify, and release resources into their surroundings. the physical-chemical conditions that surround an organism regulate metabolism as they consume resources and generate waste (begon et al. ) . ultimately, resource flows influence system dynamics of populations and communities. biogeochemistry describes the flow of matter, such as nutrients and toxins, through an ecosystem matrix, including processes such as decomposition and decay. it spans biotic and abiotic compartments through biologically mediated chemical cycling of nutrients. microorganisms play a critical role in the availability of resources by decomposing waste and processing mineral components, essentially driving nutrient cycles in ecosystems. temperature, salinity, ph, and redox generate gradients regulating distribution of organisms and their metabolism, in effect the availability of resources (schlesinger ) . availability of resources, notably nutrients, is related to population dynamics, e.g., the life cycle of organisms, and community structure, such as food webs. phosphorus, for example, is a commonly limiting nutrient in freshwater lakes that constrains productivity. while phosphorus can be introduced through external subsidies, the ecological community can influence availability of the resource internally, thereby altering community composition. certain zooplankton, for example, sequester phosphorous for their reproductive needs to the extent that they limit growth and abundance of competing species. these competitive interactions will ultimately affect water quality and physical characteristics, such as transparency and temperature profiles (elser et al. ) . physical-chemical conditions of the matrix drive enzymatic processes and affect habitat suitability and niche structure in ecosystems. olff et al. ( ) proposed an additional horizontal ecological-stoichiometry axis to supplement the vertical trophic axis in food webs (fig. ) . these frameworks build upon research in marine systems (azam et al. ) and terrestrial systems (bardgett ; wardle ) that emphasize a 'dual foundation' for food webs based on both organotrophs and autotrophs. the landscape provides the physical structure for the ecosystem matrix, including habitat niches for organisms. physical connectivity (e.g., wildlife corridors) can dictate the distribution and dispersal of organisms. as chemicals transition among media such as water, the atmosphere, and land they are modified in ways that alter their availability. landscapes support a mosaic of abiotic conditions that determine the phase space of abiotic resources, including chemical state and suitability for uptake. ecosystem engineering is the process whereby organisms influence the biophysical feedback mechanisms that structure their habitat. this can fundamentally alter ecosystem function from local to global scales (e.g., beaver dams to forest respiration). ecosystem engineers influence the matrix in which they live, rendering it more or less habitable for themselves and their competitors (jones et al. ; wright and jones ) . in australia, for example, a rabbit fence was built to confine expansion of invasive rabbits, altering patterns of herbivory that, in turn, affected evapotranspiration and regional precipitation. ultimately, this altered the microclimate and suitability of the environment for multiple organisms and processes (lyons et al. ) . feedback loops and cycles add complexity and nonlinearity to the system. they can lead to emergence of alternate stable states, with abrupt tipping points, where shifts to alternate regimes modify function and introduce chaos (scheffer and carpenter ; carpenter et al. ; huisman and weissing ; van de koppel et al. rietkerk ). ecosystem processes influence human health directly via interaction with toxins and nutrients, and indirectly via regulation of disease cycles and intensity. bioaccumulation of toxins throughout food webs poses a health threat, an example of which is dichlorodiphenyltrichloroethane (ddt), effective in controlling disease vectors but endangering animal and human health by its bioconcentration. ecosystems provide services such as sequestering toxins in wetlands and sediments, but these processes often are fragile and their disruption results in system-wide impacts. nutrient enrichment, or eutrophication, of lakes has been directly correlated with prevalence of aquatic disease agents (johnson and carpenter ) . regulation of disease is an indirect ecosystem service. however, perturbations of ecological systems can alter the regulatory process and unleash novel pathogens, demonstrated vividly by lyme disease and the dilution effect (ostfeld and keesing ) . in today's world, the biosphere is undergoing unprecedented anthropogenic ecosystem engineering, ranging from land conversion to ecological simplification and extensive biogeochemical change. the impact of these alterations spans ecosystem nodes, edges, and pathways with profound ramifications for ecosystem services and resilience. as the modified ecosystems and regimes emerge, their potential to impact human health must be understood. investigators have developed hotspot maps to characterize risk of disease emergence (jones et al. ) and threats to biodiversity (mittermeier et al. ). however, coupled socio-ecological models of risk have yet to be developed. as a network evolves, dynamic risk mandates continuous adaptive iterations to monitor emerging threats. the major drivers are direct anthropogenic land-use change, e.g., deforestation, agricultural expansion, habitat destruction, and complex indirect feedback from anthropogenic impact affecting biogeochemical cycles, e.g., nutrient cycles and climate change. the phase space for ecosystems evolves as communities are restructured. emerging systems are unstable and exhibit complex non-equilibrium dynamics and alternate states. getting ahead of an epidemic curve (fig. ) requires more than simply aggregating concepts of populations, communities, or ecosystems (schoener ). the changing network properties of the system must be monitored, along with indicators of resilience and leading indicators of collapse, if how a major disturbance is propagated or dampened through the system is to be understood. failing to comprehend the emerging topology of coupled socio-ecological systems presents a challenge of knightian uncertainty, where risk is immeasurable, and panarchy, where cause and effect are disproportionate. in these instances, disturbances can become amplified through emerging network dynamics. changes like habitat destruction and land-use/land-cover change affect the physical structure of the environmental matrix and have profound impacts on ecosystems. they jeopardize critical services, e.g., disease regulation and other, as yet unknown, ecosystem services. for example, minor disturbances from deforestation in the peruvian amazon exposed frontier effects, whereby cases of infectious disease peaked with human encroachment, but re-stabilized as humans and pathogens adapted (olson ) . it is difficult to anticipate consequences of ecosystem encroachment since the dynamics are highly variable and outcomes unpredictable. however, in this case the system exhibited altered contact and transmission rates, as well as improved habitat for malaria vectors. genetic diversity dictates adaptability. we should anticipate widespread physiological, morphological, and behavioral adaptations with land-use change, and inevitable consequences for disease emergence. geography and landscapes have long been known to play a critical role in disease, indeed the earliest disease maps by finke and humboldt date from the early victorian period (tylianakis et al. ). hence, we can anticipate that landscape changes will fundamentally alter existing ecosystem networks. changes at the landscape level, such as isolation due to habitat fragmentation, counter the trend of more highly connected systems. however, an increase in isolated systems may lead to increased genetic drift and introduce new vulnerabilities from founder effects and genetic bottlenecks. these refugia and biological corridors become hotspots for disease transmission as organisms are crowded out of the human landscape and stressed by reduced resource availability. the green revolution brought widespread alterations to global biogeochemistry. accompanying changes in agricultural practice altered the agrarian landscape-an important habitat in terms of both surface area and productivity. in this context, biogeochemistry is particularly relevant to health, given anthropogenic modification of global processes. following world war ii, the industrial efficiencies of bomb factories were adapted to production of agricultural fertilizers. as a consequence, ecological stoichiometry was radically altered. in geological time, this is a short-term experiment and it is not yet clear what the long-term implications will be for global-scale ecosystem processes. indeed, the fertilizers manufactured are typically nutrients that limit productivity. hence it is inevitable that these will impact abundance and distribution of organisms, including disease hosts and vectors. in , researchers convened by the wildlife conservation society (wcs) coined the term ''one world-one health,'' at a time of increasing global interest in connections between emerging infectious diseases and environmental stewardship. what has become the one health movement calls for interdisciplinary and crosssectoral approaches to disease prevention, surveillance, monitoring, control, and mitigation, as well as environmental conservation. the goal of improving lives, with integrated health approaches, has been embraced by veterinary, medical, public health, agricultural, and environmental health organizations in the one health initiative. this movement has helped integrate ideas from environmental, veterinary, and agricultural science with public health, and has been successful in bringing broader attention to socio-economic influences on human and animal health. ecohealth emerged in the s from an interest in connecting ecosystems and health through the original work of the international development research council (idrc) (lebel ) . the ecohealth community has since grown to include researchers from a broad range of disciplines, all of whom share an interest in the intersection of ecology and health. humans must be included in ecohealth models and wildlife in one health models. otherwise, our understanding of disease risk cannot be complete. conceptual and mathematical models from the social sciences and public health can usefully be combined with those developed for agriculture and ecology. thus, the coupled socio-ecological models will allow characterization of emerging systems, with the challenge of capturing non-linear complex behaviors. in conclusion, the dimensions of ecological approaches to public health that we propose in this chapter are, in essence, networks of population dynamics, community structure, and ecosystem matrices incorporating concepts of complexity, resilience, and biogeochemical processes. case studies disease emergence can strongly impact the abundance and diversity of wildlife populations. the dynamics of wolf and moose populations on isle royale is a classic case study. the single predator-prey dynamic is unique in its simplicity and is one of the longest studied. the system has never achieved equilibrium and cannot be explained either by top-down control of moose abundance by wolf predation or bottom-up control of wolf abundance by moose availability (vucetich et al. ) . moreover, the system exhibits both influences, with episodic disturbances from disease and climate. the introduction of parvovirus by a domestic dog caused the wolf population to crash in . subsequently, the moose population exploded which impacted balsam fir, their winter food. consequently, in the moose population crashed during a harsh winter. moose are mega-herbivores (owen-smith ) that grow sufficiently large to escape predation from wolves, so wolves are only able to prey on the young and infirm. the moose are vulnerable to ticks, which contributes to poor body condition and makes them more vulnerable to wolf predation. ultimately, the dynamics of an invasive disease agent influenced community structure, as did predation, resource availability, parasitism, abiotic conditions, and genetic diversity. these events challenged the certainty of predictive models of population dynamics and community structure. this case study illustrates the difficulty of modeling eids in relation to ecosystem dynamics. correlation of the incidence and intensity of cholera, primarily a waterborne disease, with environmental parameters, e.g., temperature, salinity, nutrients, conductivity, and other factors, including rainfall, extreme weather events, and with access or lack of access of the populace to safe water and sanitation has been studied by many investigators over the past years. the observation of colwell and huq ( ) that the causative agent of cholera, vibrio cholerae, is a commensal of zooplankton, predominantly copepods, led to examination of the annual incidence of cholera in bangladesh. controlling factors were determined to be water temperature and salinity, but also relationship to the annual cycle of plankton (colwell ) . the annual bimodal peaks of cholera in bangladesh (spring and fall) correlated with plankton blooms in the spring and fall, with copepods proving to be a vector for v. cholerae (de magny et al. ) . further studies, employing satellite remote sensing to monitor chlorophyll, sea surface temperature, and sea surface height in the bay of bengal, provided useful models of the relationship of cholera and climate (lobitz et al. ) . refinement of the models and detailed analyses of the river system of the ganges delta led to further and more detailed characterization of the drivers of the spring and fall cholera outbreaks, namely rainfall, river height and flow, and salinity (jutla et al. ) . cholera, and very likely other waterborne diseases, can be tracked to their environmental source (jutla et al. ) . thus, ecology of the v. cholerae proved to be key in understanding incidence of the disease (colwell et al. ; lipp et al. ) . based on ecology and evolution of v. cholerae, predicting cholera incidence in various regions of the world is promising. in fact, preliminary results demonstrate effectiveness of regional hydroclimatology combined with satellite data for cholera prediction models for coastal regions in south asia and sub-saharan africa, providing lead time to strengthen intervention efforts before the seasonal outbreaks of cholera occur in these endemic regions. the role of wildlife and livestock in the transmission of infectious agents to humans has been recognized for decades (karesh et al. ). zoonoses such as rabies remain endemic in wildlife and continue to spillover to people as they have done for probably centuries. however, the importance of wildlife from which pathogens are transmitted has become critical in the era of eids. the majority of eids are zoonotic and originate in wildlife (jones et al. ). pathogens such as nipah virus (niv), sars coronavirus, and ebola virus originate in wildlife species from tropical or subtropical regions, where human population density is high, and rapid changes to the environment drive increasing risk of spillover. the role of ecology in understanding patterns of zoonotic disease emergence is significant and ecologists need to be integrated into one health efforts. traditional epidemiological investigations of emerging zoonoses focus on the network of human cases affected by an eid, tracing back to origins and examining risk behavior. unfortunately, studies tend to view the role of wildlife as a risk factor for spillover and rarely involve detailed studies of wildlife population dynamics. for example, fruit bats were identified as the reservoir of nipah virus (niv) in malaysia and are, therefore, a risk factor for its emergence elsewhere. in malaysia, niv first emerged in pig farms close to fruit bat habitats. it was hypothesized that the intensive nature of the farms were the trigger for its emergence (chua et al. ). an alternative hypothesis was that bats brought the virus into the country from nearby sumatra following forest fires there during a severe el nino event (chua et al. ) . a collaborative group including wildlife biologists, veterinarians, virologists, mathematical modelers, physicians, and epidemiologists collected and analyzed data on the hunting of bats, pig population dynamics at the index farm, large-scale movement of fruit bats and the capacity of the virus to survive in urine, saliva, and fruit juices (pulliam et al. ) . this work was able to demonstrate that the continued presence of bats in the index farm region, and the particular dynamics of intensive production allowed the virus to invade the pig farm, produce a partially immune population of pigs, then re-invade to create a long-term exposure of pig workers, and the large-scale outbreak observed (pulliam et al. ) . early epidemiological studies of the emergence of niv in bangladesh identified drinking of date palm sap as a risk factors, and suggested that this might be due to contamination of the collecting pots by fruit bats (luby et al. ) . subsequent investigations involved wildlife biologists who used infrared cameras to confirm contamination in the field (khan et al. ) , and conducted longitudinal surveillance of bat populations to examine whether seasonal patterns exist that could be used to estimate risk. these studies demonstrate the value of analyzing 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infectious disease: use of remote sensing for detection of vibrio cholerae by indirect measurement foodborne transmission of nipah virus land-atmosphere interaction in a semiarid region: the bunny fence experiment hotspots: earth's biologically richest and most endangered terrestrial ecoregions. conservation international, cemex sa de cv, agrupación sierra madre, mexico city murray bg ( ) can the population regulation controversy be buried and forgotten the strategy of ecosystem development parallel ecological networks in ecosystems deforestation and malaria in mâncio lima county biodiversity and disease risk: the case of lyme disease megaherbivores: the influence of very large body size on ecology agricultural intensification, priming for persistence and the emergence of nipah virus: a lethal bat-borne zoonosis self-organized patchiness and catastrophic shifts in ecosystems catastrophic regime shifts in ecosystems: linking theory to observation mechanistic approaches to community ecology: a new reductionism? habitat modification alters the structure of tropical host-parasitoid food webs do alternate stable states occur in natural ecosystems? evidence from a tidal flat scale dependent feedback and regular spatial patterns in young mussel beds predicting prey population dynamics from kill rate, predation rate and predator-prey ratios in three wolf-ungulate systems communities and ecosystems: linking the aboveground and belowground components a review of trait-mediated indirect interactions in ecological communities evolution and measurement of species diversity in: frumkin h (ed) environmental health: from global to local the concept of organisms as ecosystem engineers ten years on: progress, limitations, and challenges acknowledgments we thank alexa frank (ecohealth alliance) and norma brinkley (university of maryland) for invaluable assistance in the preparation of this chapter.the human environment interface key: cord- - ce xhjo authors: li, chun; he, jianhua; duan, xingwu title: the relationship exploration between public migration attention and population migration from a perspective of search query date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: ce xhjo rapid population migration has been viewed as a critical factor impacting urban network construction and regional sustainable development. the supervision and analysis of population migration are necessary for guiding the optimal allocation of urban resources and for attaining the high efficiency development of region. currently, the explorations of population migration are often restricted by the limitation of data. in the information era, search engines widely collect public attention, implying potential individual actions, and freely provide open, timelier, and large-scope search query data for helping explore regional phenomena and problems. in this paper, we endeavor to explore the possibility of adopting such data to depict population migration. based on the search query from baidu search engine, three migration attention indexes (mais) are constructed to capture public migration attention in cyber space. taking three major urban agglomerations in china as case study, we conduct the correlation analysis among the cyber mais and population migration in geographical space. results have shown that external-mai and local-mai can positively reflect the population migration inner regions and across regions from a holistic lens and that intercity-mai can be a helpful supplement for the delineation of specific population flow. along with the accumulation of cyber search query data, its potential in exploring population migration can be further reinforced. along with the rise of a city network, which is constructed under the push of different kinds of urban elements flows, the interactions among different cities have been emphasized in the planning of urban areas, including the interaction of population, material, information, technique, etc. hereinto, population interaction or population migration is one of the most important aspects. the floating of population is not only the flowing of individual human but also the transfer of demand, information, and technique carried by individuals [ , ] . they discriminately impact economic, social, and political development of both resettled areas and out-migrating areas [ , ] . timely measuring and analyzing of population migration are particularly crucial for suitably planning urban space and distributing urban resources. related explorations on population migration have been concerned as hotspots since the s. a larger body of researches have been conducted, such as the labor market performance, social and physical status of migration [ ] [ ] [ ] , the causes of migration flow [ ] [ ] [ ] , the consequent impacts of migration [ ] [ ] [ ] , the changing migration policies [ ] [ ] [ ] , the classification research of population migration [ , ] , the spatial pattern of population migration [ ] , etc. these researches have been conducted mainly based on three kinds of data: national censuses data, regional field survey data, and cyber big data. in the traditional migration researches, population censuses and field survey are the principal sources to provide population data [ , ] . for instance, zhu [ ] explored the determined factors in urban area which influence migrants' settlement intention based on the data from a survey on the floating population in the coastal area of fujian province. he et al. [ ] adopted national census data to examine the distinctive spatial patterns of floating and hukou population and evaluated their consequent impact on chinese urbanization and industrialization. with the development of cyber space and the popularization of personal mobile termination, numerous researches have implemented under the assistance of data from cyber space exploration of the change, characteristic, and pattern of population migration [ ] [ ] [ ] [ ] . for instance, blumenstock [ ] analyzed migration pattern based on mobile phone records and revealed more subtle patterns that were not detected in the government population survey. zagheni et al. [ ] used geolocated data for about , users of the social network website "twitter" to predict turning points in migration trends and to improve the understanding of migrant populations. those researches have contributed largely to promoting the understanding of the progress of population migration and their impact. however, the deficiencies in migration data still exist. studies based on national censuses data can explore the migrants in a large range but with a relatively large time interval of ten years, which hinders the short time-series analysis of population migration, and little can be inferred for specific years between censuses and for recent trends [ ] . the researches based on field survey can provide detailed migration information, but it asks for a lot of time, manpower, and material resource to deploy, which are expensive for many researches. simultaneously, the field survey often has a certain spatial location and cannot cover a large spatial scope. the increasing cyber data has opened up a new opportunity to deepen our understanding of population migration. however, studies based on the network big data always need to deal with extensive data and complicated procedures in acquiring and processing the data. at the same time, some data sources are not available openly, such as cellphone signal data and gps data of resident activities, because those types of data include much individual private information that is protected by national law. a type of data with open, timelier, and easy-taking characteristics is necessary for effectively investigating the migration population. with the growing application of search engine in cyber space, search query data has been brought out to reflect the preference of public attention, which is generated from the personal behavior of internet search. this kind of data with opening and timelier characteristic has provided effective support for analyzing regional phenomena and problems [ ] [ ] [ ] [ ] . in such context, the concern is triggered about its applicability in population migration research. in current information era, most people tend to take migration after an inquiry of destinations. web search engine as the most widely used internet tools provides massive information to the migrants and obtains relevant public attention on the specific subject of migration. the relationship between internet search query data and population migration deserves more attention. however, the relationship between them is still unclear and there are a number of questions to be raised: can the search query data generated from migration-related information search offer some clues about population migration? if they can, how are they related? do cites with higher cyber search quantity have a larger migration population than the cities with lower search quantity? based on these questions, this paper endeavors to answer them and to propose a new angle to analyze population migration. a hypothesis can be made that the search queries generated from individual migration-related search can positively reflect population migration. based on the search query data from baidu search engine, we construct a series of migration attention indexes (mais) to explore public attention on migration. taking three main urban agglomeration areas of china as study area, the correlation analysis has been utilized to explore the relationship between mais and population migration to test the hypothesis. this paper is organized as follows. section introduces the study area and data. section elucidates the methodology of this paper, including the method and indicators that we applied in this paper. section reports the result of correlation analysis between of mai and population migration. section conducts further discussion based on the results in our study area. last, we conduct the conclusion of this paper. to verify the relationship between search query data in cyber space and population migration in geographical space, we select three urban agglomerations in china as case study: beijing-tianjin-hebei metropolitan region (bth), the yangtze river delta (yrd), and the pearl river delta (prd). there are cities located in these regions, cities from bth, from yrd, and from prd, as shown in figure . these regions are chosen based on the following reasons: ( ) extensive population migration can be detected in these areas. in , the migration population in these areas has reached more than million in total, accounting for . % in china. exploration of migration in these regions can avoid the influence of random migration under the support of large quantities. ( ) these regions with relatively higher internet penetration offer adequate search query data. by the end of , internet penetrations of core cities in those three urban metropolitan areas are separately . % for beijing, . % for shanghai, . % for guangzhou, and . % for shenzhen. more widespread application of the internet can be identified in almost all the provinces cover bth, yrd, and prd [ ] . ( ) to verify the relationship between search query data in cyber space and population migration in geographical space, we select three urban agglomerations in china as case study: beijing-tianjin-hebei metropolitan region (bth), the yangtze river delta (yrd), and the pearl river delta (prd). there are cities located in these regions, cities from bth, from yrd, and from prd, as shown in figure . these regions are chosen based on the following reasons: ( ) extensive population the data used in this paper include the population migration data, search query data, and socioeconomic data. ( ) there are three kinds of population migration data used in this study: the net inflow population, intercity population flow, and the floating population. the net inflow population delineates the total population migrated into the city during a specific period. intercity population flow is the population migrate from the original city to the terminal city. based on the prevalent use of series tencent's applications (e.g., wechat is the most used software for . % of chinese netizens), more precise expression on the migration of population in china can be provided by tencent migration map under the support of enormous user base. considering the merit of tencent migration map and avoiding the self-certification of baidu, we obtained the net inflow population and intercity population flow from tencent migration map (https://heat.qq.com/qianxi.php) through web crawler technology. due to the specific hukou policy in china (which has been regarded as the central mechanism underlying the unsettled nature of the floating population), the floating population has been defined as the population living in the objective city more than six months without local registered hukou [ ] . it was obtained through the deviance calculation of permanent residential population and household population in the local city, which were collected from regional statistical bureaus. ( ) we obtain the search query data based on the support of baidu search engine, which is the most widely used search engine in china and freely provides the search trend of objective terms through baidu index (http://index.baidu.com/). the average daily queries of each migration keyword versus the name of the city (e.g., job + beijing) from january to december were collected based on baidu index. ( ) relevant socioeconomic data were acquired from regional statistical bureau, including the tertiary industrial output-value, participant rate of urban basic medical care system, the number of schools, etc. the migration reasons were collected from the dynamic monitoring survey of china's migration population in , which was conducted by the national health and family planning commission of china. we endeavor to verify the relationship between public attention on migration which was provided by search query in cyber space and the population migration in geographical space. migration attention indexes (mais) are proposed to express public attention on migration comprehensively. based on the different original location of migration search, we construct three mais as local-mai, external-mai, and intercity-mai to delineate the public attention generated from local city, attention from external areas, and attention flow among urban areas; then, the correlation analysis is conducted between mais in cyber space and urban migrants in geographical space to further verify the aforementioned hypothesis. the framework of this paper can be illustrated in figure . specially, the net inflow population, intercity population flow, and the floating population have been collectively adopted to depict the movement of population in this paper. the definition of migration for them can be separately clarified as follows: the net inflow population of a city is defined as population that the city has received from the external areas, which is the result of movement of people with different origins and the same destination; the intercity population flow is also defined as the movement of people, which happens among different cities; and the floating population of a city is defined under the hukou policy of china (which has been regarded as the central mechanism underlying the unsettled nature of the floating population), of which the migration can be explained as the change in the place of personal residence. int. j. environ. res. public health , , x of to verify the hypothesis that the migration-related search queries from individual users can positively reflect the population migration, three issues should be concerned: ( ) what are the main driving factors cause population migration; ( ) how to express those factors in cyber space through search query data; and ( ) how to synthesize those search query data to comprehensively express public attention on migration in cyber space. for the first issue, based on the dynamic monitoring survey of china's migration population in , we have conducted the statistic of population percentage on different migration reasons to confirm the main factors which cause population migration. for the second issue, a series of search keywords expressing different migration reasons has been selected. the baidu index of keywords versus the name of city has been collected to reflect the public attention on migration in cyber space. for the third issue, migration attention indexes (mais) have been constructed to integrate public attentions generated based on different migration reasons. to pointedly select search keywords that load public attention on migration. first, we confirm the main reason for population migration based on the dynamic monitoring survey of china's migration population in . the percentage statistics of migrant population based on diverse migration reasons in the three different urban agglomerations are deployed. the results have been shown in table ; we can see that work and trade, that study and training, that accompanying transferring of family members, and that relocation are the main migration factors in the study area. the percentages of population who migrate for the four reasons separately occupy . %, . %, and . % in beijing-tianjin-hebei metropolitan region, the yangtze river delta, and the pearl river delta. to verify the hypothesis that the migration-related search queries from individual users can positively reflect the population migration, three issues should be concerned: ( ) what are the main driving factors cause population migration; ( ) how to express those factors in cyber space through search query data; and ( ) how to synthesize those search query data to comprehensively express public attention on migration in cyber space. for the first issue, based on the dynamic monitoring survey of china's migration population in , we have conducted the statistic of population percentage on different migration reasons to confirm the main factors which cause population migration. for the second issue, a series of search keywords expressing different migration reasons has been selected. the baidu index of keywords versus the name of city has been collected to reflect the public attention on migration in cyber space. for the third issue, migration attention indexes (mais) have been constructed to integrate public attentions generated based on different migration reasons. to pointedly select search keywords that load public attention on migration. first, we confirm the main reason for population migration based on the dynamic monitoring survey of china's migration population in . the percentage statistics of migrant population based on diverse migration reasons in the three different urban agglomerations are deployed. the results have been shown in table ; we can see that work and trade, that study and training, that accompanying transferring of family members, and that relocation are the main migration factors in the study area. the percentages of population who migrate for the four reasons separately occupy . %, . %, and . % in beijing-tianjin-hebei metropolitan region, the yangtze river delta, and the pearl river delta. due to the transferring of family members always accompanying family relocation [ ] , we have viewed them as one perspective and marked as relocation. therefore, three main reasons for population migration have been confirmed as work and trade, study and training, and relocation. to better exhibit and exploit search query data, relevant search exploit services based on search query data are produced, typically as google trend (www.google.com/trends/) and baidu index (http://index.baidu.com/). a series of researches have been conducted to analyze data from google trend and baidu index; the robustness and effectiveness of them have been assessed [ ] [ ] [ ] . in china, compared to google, which is the largest search engine in the world, baidu shares more internet search engine market. in , there are million netizens in china and the number of search engine users has reached million [ ] . hereinto, baidu shares . % of the internet search engine market, which is more than google china. especially, vaughan and chen [ ] collected and compared the data from google and baidu and found that baidu index can offer more search volume data than google trend did in china. under such context, the baidu index is employed in this paper to obtain public search attention in the cyber space. focusing on the three main migration reasons, we endeavor to confirm the search keywords which reflect public attention on migration. the confirmation of search keywords is comprehensively confirmed under five steps. first, according to the least effort principle in network information retrieval behaviors, users incline to choice the search keywords in their common language with brief and straightforward features [ , , [ ] [ ] [ ] [ ] . we set the candidate keywords with brief structure and expressed them in chinese. second, the specific content of candidate keywords was derived from the three main migration reasons. relevant search terms for them were selected by brainstorming common words used in searching for migration and review of related literature [ , [ ] [ ] [ ] . third, we have compared the daily average search query data of designated search keywords with similar words during the same period to confirm that the selected keywords are the most popular search keywords in the related aspects. for example, "租房 (house renting)" has been compared to "出租 (rent)" and "租赁 (lease)"; collecting and organizing their average daily baidu index can find that "house renting"( , ) gets much more attention than "rent"( ) and "lease"( ). fourth, we sift the candidate words to follow the principle of search query data for each keyword in each city to be delineated as a sequential time series with a yearly resolution. fifth, the correlation analysis between the last candidate keywords has been conducted and the one with a high correlation with others has been removed to reduce data redundancy. through the comprehensive consideration of keyword selection, the last keywords can be viewed as not only representing the meaning itself but also including some clues for other potential keywords. finally, six chinese keywords from baidu index have been confirmed to express public attention on migration in cyber space as list in table . the migration attention indexes (mais) are designed to comprehensively express public attention on migration in cyber space comprehensively. first, we combine the candidate search keywords with the name of objective cities to obtain the cityward migration keywords, such as "school + beijing", "house price + shanghai", "recruitment + shenzhen", etc.; second, the average daily search volume of these cityward keywords are acquired based on baidu index from january to december ; third, the population percentages of different migration reasons are viewed as index weight to synthesize the corresponding baidu index into mais; fourth, according to the origin location of baidu index, the local-mai, external-mai, and intercity-mai are separately constructed to express public migration attention on objective cities from internal area of the objective cities, external areas, and other specific cities. the relationship among those indexes can be depicted as follows: where i is the objective city, j is the original city, mai i is the total migration attention city i has achieved from all regions, and local-mai i and external-mai i are separately the total migration attention city i has received from the urban internal area and external areas. intercity-mai ij is the public migration attention derived from city j to city i. the formula of those indexes can be shown as follows: where bi n is the average daily volume of baidu index about different search keywords under migration reason n; w in and w ijn are the weights of bi n , which are defined by the proportion of people who migrate into city i for this reason; and mai max is the max absolute value of mai indicators. to investigate the relationship between public migration attentions in cyber space and population migration in geographical space, we conduct the correlation analysis between mais and urban migrants. in the cyber space, local-mai, external-mai, and intercity-mai were selected to represent public migration attentions with different originations to objective cities; in geographical space, floating population, inflow population, and intercity population flow were collected. regarding the diverse kinds of migration and different definition of mais, the correlation analysis have been conducted from three aspects: ( ) the correlation between local-mai and floating population, which reflects the relationship between migration attention generated from the local city and actual floating population inside the city; ( ) the correlation analysis between external-mai and inflow population, which explores the relationship between migration attentions received from the external areas and actual inflow population of the objective city; and ( ) the correlation analysis between intercity-mai and intercity population flow, which investigates the relationship between cyber migration attention flows and the actual population flows in the geographic space. pearson correlation coefficient is employed to test such correlations, the formula can be shown as follows: where r is the correlation coefficient of the two indexes and n is the number of cities. furthermore, we inquired about the relationship between urban external-mai in cyber space and urban comprehensive attractiveness for migrants (uam) in geographical space to further test the validity of the proposed indicators. based on the push-pull theory which has been widely used in analyzing migration action and willing [ ] [ ] [ ] [ ] , we confirmed the uam from urban pull perspective. the major migration reasons confirmed by the dynamic monitoring survey of china's migration population have been employed as reference in confirming the objective content of uam, including work and business, study and training, and relocation. the three aspects separately correspond with the three major migration reasons as job opportunity and income level, living condition, and educational opportunity of children. based on the data availability principle and integrated analysis of previous studies, eight indicators with respect to three aspects of urban pulling power have been selected as shown in table . from job and income perspectives, tertiary industrial output-value (tiv) [ ] and urban residents' per capita disposable income (ipc) [ ] were employed to reflect urban job opportunities and income level; unemployment rate (ur), participant rate of urban basic medical care system (rbm) [ ] , and per capita living area (lpc) [ ] were utilized to expose the living condition of local residents; number of regular primary schools (psn), number of regular secondary schools (ssn), and number of university (un) were applied to reveal educational opportunity for migrants' children [ ] . last, we adopted the principal component analysis (pca) to integrate the index system and to obtain the indicator which reflects urban comprehensive attractiveness for migrants. the components with eigenvalues greater than and the cumulative ratio of total variance greater than % are extracted and rotated with the varimax method in spss . (international business machines corporation, new york, usa), so that each factor has the minimum number of high load variables, which can be expressed as follows: where uam k is urban comprehensive attractiveness for migrants of city k; m is the number of major components which make the cumulative ratio of the total variance greater than %; a i contributes the major components i to uam of the city; n is the number of indexes; c ij is the contribution of index j to the major components i; and x * kj is the standardized value of index j in city k. according to the definition of mai, the migration tendency of the person from the outside areas can be conveyed through external-mai. under the assistance of relevant migration data from the tencent map, we engaged in exploring the relationship between external-mai and urban migration population. pearson correlation coefficient was adopted to reveal the relationship between them; the results have been shown in table and figure . as we could observe, there are significant positive correlations between external-mai and population migration in the three urban agglomerations. the pearson coefficients are . , . , and . separately in bth, yrd, and prd, which has a holistic coefficient of . . all of them have passed the significance test at % confidence level. focused on their spatial heterogeneity, the cities of bth has the highest correlation. corporation, new york, usa), so that each factor has the minimum number of high load variables, which can be expressed as follows: where uamk is urban comprehensive attractiveness for migrants of city k; m is the number of major components which make the cumulative ratio of the total variance greater than %; ai contributes the major components i to uam of the city; n is the number of indexes; cij is the contribution of index j to the major components i; and x * kj is the standardized value of index j in city k. according to the definition of mai, the migration tendency of the person from the outside areas can be conveyed through external-mai. under the assistance of relevant migration data from the tencent map, we engaged in exploring the relationship between external-mai and urban migration population. pearson correlation coefficient was adopted to reveal the relationship between them; the results have been shown in table and figure . as we could observe, there are significant positive correlations between external-mai and population migration in the three urban agglomerations. the pearson coefficients are . , . , and . separately in bth, yrd, and prd, which has a holistic coefficient of . . all of them have passed the significance test at % confidence level. focused on their spatial heterogeneity, the cities of bth has the highest correlation. applying the principal component analysis, we obtained uam of target cities based on the statistical data; the correlation study was deployed between the comprehensive uam and external-mai. as shown in table and figure , we could observe a significant correlation between the uam and external-mai in the study areas. the coefficients of the whole area, bth, yrd, and prd are separately . , . , . , and . . the high correlation between them illustrated that urban received external-mai is highly correlated to the attractiveness of urban itself. the relationship between such a cyber-based index and a traditional statistic-based index can be implied. applying the principal component analysis, we obtained uam of target cities based on the statistical data; the correlation study was deployed between the comprehensive uam and external-mai. as shown in table and figure , we could observe a significant correlation between the uam and external-mai in the study areas. the coefficients of the whole area, bth, yrd, and prd are separately . , . , . , and . . the high correlation between them illustrated that urban received external-mai is highly correlated to the attractiveness of urban itself. the relationship between such a cyber-based index and a traditional statistic-based index can be implied. furthermore, the pearson correlation coefficients between the selected indexes and external-mai have been calculated, as shown in table . we can see that all the two indexes for job opportunities and income levels have the highest correlation with external-mai in the study area. for the living condition perspective, a positive correlation can be observed between the participant rate of urban basic medical care system and external-mai in bth and yrp. however, significant correlations cannot be observed between the unemployment rate per capita living area with external-mai. paying attention to the education opportunities, significant correlations can be found in bth and yrd between the three educational indexes and population attention index. in prd, only the number of primary schools significantly correlates with external-mai. in the three urban agglomerations, the strongest correlations are depicted between the tertiary industrial output-value and external-mai, which reflect job opportunities in the areas being conventionally attractive for the potential migrants. insignificant low correlation between the unemployment rate per capita living area with external-mai can be detected. furthermore, the pearson correlation coefficients between the selected indexes and external-mai have been calculated, as shown in table . we can see that all the two indexes for job opportunities and income levels have the highest correlation with external-mai in the study area. for the living condition perspective, a positive correlation can be observed between the participant rate of urban basic medical care system and external-mai in bth and yrp. however, significant correlations cannot be observed between the unemployment rate per capita living area with external-mai. paying attention to the education opportunities, significant correlations can be found in bth and yrd between the three educational indexes and population attention index. in prd, only the number of primary schools significantly correlates with external-mai. in the three urban agglomerations, the strongest correlations are depicted between the tertiary industrial output-value and external-mai, which reflect job opportunities in the areas being conventionally attractive for the potential migrants. insignificant low correlation between the unemployment rate per capita living area with external-mai can be detected. the results of correlation analysis between local-mai and local floating population have been shown in table and figure . we can see that, no matter in the whole study area or the individual urban agglomeration, high correlation coefficients were gained. especially in the yrd, the relevant coefficient has arrived at . . prd has a relatively lower value but is still higher than . . divided by the median value of local-mai and local floating population, the cities in the study area can be divided into four types. thereinto, . % of them has high-high or low-low features. for the cities with higher-than-average floating population and higher-than-average local-mai, there are three located in the bth (beijing, tianjin, and baoding), two in yrd (shanghai and suzhou), and two in prd (shenzhen and guangzhou). to further excavate information from mai, the relationship between local-mai and external-mai has been explored; the results are shown in figure . there is a highly positive correlation between the two indexes, of which the r is . and p is . . it is shown that the city with higher local-mai also has a higher external-mai to further excavate information from mai, the relationship between local-mai and external-mai has been explored; the results are shown in figure . there is a highly positive correlation between the two indexes, of which the r is . and p is . . it is shown that the city with higher local-mai also has a higher external-mai to further excavate information from mai, the relationship between local-mai and external-mai has been explored; the results are shown in figure . there is a highly positive correlation between the two indexes, of which the r is . and p is . . it is shown that the city with higher local-mai also has a higher external-mai to explore the relationship between intercity-mai and intercity population flow, the results have been shown in table and figure . as we could notice, the average value of intercity-mai is . , guangzhou-shenzhen has the highest intercity-mai at . ; and shenzhen-chengde has the lowest index of . . for the individual urban agglomeration, the intercity-mai among beijing, tianjin, and shijiazhuang has the highest top three values in bth. the same level of intercity-mai to explore the relationship between intercity-mai and intercity population flow, the results have been shown in table and figure . as we could notice, the average value of intercity-mai is . , guangzhou-shenzhen has the highest intercity-mai at . ; and shenzhen-chengde has the lowest index of . . for the individual urban agglomeration, the intercity-mai among beijing, tianjin, and shijiazhuang has the highest top three values in bth. the same level of intercity-mai can be found in yrd for shanghai, hangzhou, and suzhou. in prd, such level interactions are observed between guangzhou, shenzhen, and foshan. under the correlation analysis of these two indexes, a moderately positive correlation can be observed in the study area (see table ). for the three urban agglomerations, prd has the highest correlation among them and the correlation in bth and yrd represents a relatively lower level. there are pairs of cities that have a high-high correlation pattern (high intercity-mai and high intercity population flow), there into pairs in bth, pairs in yrd, and pairs in prd; pairs of cities exhibited the low-low correlation pattern, of which, in bth, yrd, and prd, are separately , , and . these two kinds of correlation patterns occupy % of the total. although relevant correlation coefficients of intercity-mai are relatively limited, it can capture the interaction trend of population flow at an acceptable level. population flow at an acceptable level. three uas bth yrd prd coefficient . . . . sig ( -side) . . . . the massive population migration is the specific phenomenon and the inevitable driving force promoting the urbanization of population in china and many developing countries. the collection of urban mais can obtain the public intention of migration based on individual search actions and can offer exploration of population migration. depending on the mais, we analyzed the correlation relationship between local-mai and external-mai; a high correlation has been discovered. it implied that the city with relatively higher local-mai has a higher external-mai. migration may be active in the high-high cities, such as shanghai, beijing, and shenzhen. according to the dynamic monitoring survey of china's migration population in , the proportions of floating population inside these three cities separately reached . %, . %, and . %, which are much higher than the average value of china at . %. besides, they have separately occupied . %, . %, and . % (ranked top ) of the whole inflow population of the three urban agglomerations, which has the most dynamic the massive population migration is the specific phenomenon and the inevitable driving force promoting the urbanization of population in china and many developing countries. the collection of urban mais can obtain the public intention of migration based on individual search actions and can offer exploration of population migration. depending on the mais, we analyzed the correlation relationship between local-mai and external-mai; a high correlation has been discovered. it implied that the city with relatively higher local-mai has a higher external-mai. migration may be active in the high-high cities, such as shanghai, beijing, and shenzhen. according to the dynamic monitoring survey of china's migration population in , the proportions of floating population inside these three cities separately reached . %, . %, and . %, which are much higher than the average value of china at . %. besides, they have separately occupied . %, . %, and . % (ranked top ) of the whole inflow population of the three urban agglomerations, which has the most dynamic migration in china. the predominant roles of them in attracting population outside the city are declared. active migration movement can be detected to support the hypothesis derived from the correlation relationship between local-mai and external-mai. analyzing the correlation of external-mai with uam, the reasonability of external-mai can be verified through the high correlation with conventional statistics analysis. based on the push-pull theory of migration, in the cities with higher urban pulling force, more influx of population can be observed. through the calculation of uam, which depicted urban pulling force, the city with higher external-mai can observe higher uam. the feature of external-mai coincides with the setting of push-pull theory. further, exploring the relationship between external-mai and the indexes which reflect urban migration attractiveness, there are significant correlations between tertiary industrial output-value and urban residents' per capita disposable income with the external-mai in the whole study area. most of the cities with higher job opportunities and income levels receive more migration attentions from the outside area. this finding coincides with the dynamics monitoring survey of migration population suggesting a migration reason in table (work and trade as the predominant migration reason), which can represent the ability of mai indexes in capturing the impact of migration reasons. with respect to the indexes described urban living conditions, there are no significant correlations between the population migration attention and unemployment rate or per capita living area, this results may correspond to the great exception of potential migrants for their future urban condition, which can be explained by the todaro migration model from the perspective of development economics. todaro migration model argues that the migration of population is based on the "expected profit" of migrants. the hardships in urban life have not obtained enough attention from potential migrants, particularly for the rural-urban migrants who lack the necessary information as they enter a new different world [ ] . further, the more schools a city has, the more public migration attention it receives. the positive correlation existing between the education indexes (the number of primary schools, secondary schools, and universities) and external public migration attention exposes that the educational opportunities also intensify the level of urban migration attention. in prd, the focus of educational concern only derives from the consideration of secondary schools; significant correlation has not been observed between the number of the other two levels of schools in the area, which may be attributed to the relatively lower education level of guangzhou province (the administrative province that prd belongs to) than the other two urban agglomerations. besides, we further adopted the neoclassical theory in population migration to explore the reasonability of mais. the per capita disposable income of urban residents, which has been viewed as the direct index depicting the possibility for migrants to improve economic benefit, has been adopted to conduct the correlation analysis with external-mai; the results have shown that the external-mai has significant positive correlation with the per capita disposable income of urban residents (with the correlation coefficients . , . , . , and . separately in the whole study area, in bth, in yrd, and in prd). the reasonability of mais can be further identified. with the correlation analysis of external-mai and urban migration population, we could observe a significantly positive correlation. the resource endowment gap between different urban areas (e.g., economic development level, environmental quality, promotion of opportunities for individuals, etc.) triggers personal develop exception and forges migrant needs in flowing among diverse regions [ , ] . collecting information about the targeted city by employing the search query engine is an efficient and low-cost approach to supplement requisite information before deploying actual migration to external areas. as noted as the correlation results of external-mai and urban inflow migrants in the study area, we can accept the hypothesis that the migration-related search queries from individual users were able to positively reflect urban inflow migrants. external-mai can be applied to reflect urban inflow migrants on the annual scale. the high correlation between local-mai and the floating population inside cities was a signal to prove their close relationship. nowadays, the floating population inner city has become an influential part in enacting urban planning and policy. generally speaking, the floating population lived with relatively weaker urban amenities than the local population [ , ] . the desire of improving current conditions was more intensive for them, which was delineated by the high demand for new job opportunities, study chance, and the possibility of improving living quality, etc. driven by such basic needs, the corresponding search query can be brought into the cyber space and raises the high correlation between local-mai and floating population inside the city. intercity migration has already become one of the significant migration models in current china. we analyzed the correlation between intercity-mai and intercity population flow in ; a similar positive correlation can be observed as . (p-value . ) in the whole area. the results show that the representativeness of intercity-mai for population flow between different cities was effective, but the correlation relationship was relatively limited. it might be caused by two main reasons: ( ) the selection of search keywords cannot cover every reason for migration flows. a unique keyword system may exhibit some deviation in reflecting the driving force of every population flow interaction; ( ) migration movement has a lagging feature. it may happen a few months, years, or a much longer time after the search action. it also may be canceled or indefinitely delayed after information acquisition through searching, which makes the relatively lower correlation between intercity-mai and intercity population inflow. generally speaking, the correlation between intercity-mai and population flow is still on an acceptable level. it can be a supplement for the population flow research of insufficient data. in future work, the construction of a targeted search keywords system for objective population flow can be adopted to remedy such drawbacks. besides, for the three mai indexes, the different correlation coefficients in the three urban agglomerations revealed that regional disparity exists. we calculated the variance (var) and coefficient of variation (cv) of relevant correlation coefficients of three mai indexes, as shown in table . it can be seen that all the vars are lower than . and that all the cvs are lower than %. the robustness of external-mai, local-mai, and intercity-mai in reflecting population can be partly ensured in the study area. furthermore, we have tested the significance of slope of the three trend lines, which were separately fitted based on external-mai and inflow population, local-mai and floating population, and intercity-mai and population flow to identify whether mai indexes could steadily reflect the migration situation in different urban agglomerations. all the significances of slopes have been rejected by significant testing at a significant level of . (sig = . , . , and . for external-mai, local-mai, and intercity-mai). the null hypothesis could be accepted as there is no significant deviance between the slopes. although the representations of mai are diverse in different regions, the deviances are nonsignificant. migration population has immense potential to push urbanization process in current china and other developing countries. exploration of population migration based on multisource data can bring more information about the noticeable driving force of urban development. in the information and network era, the mai indexes can reveal how the public put their attention on migration-related items. based on the cyber-based indexes, we explore the relationship between public migration attention in cyber space and urban migration population in geographical space inner region, across region, and between regions. the results can answer the questions mentioned in the introduction that search query data based mai indexes can positively reflect the situation of migration population inner region and across region and, for the population flow, that it is an alternative supplement and support when relevant data is deficient. population migration is a complex process driven by diverse forces; this paper conducted a series of analyses from the perspective of search query data in cyber space. however, some limitations exist: first, the selection of continuous search keywords is limited by the short period of data acquisition from the search query engine. following the incremental collection of search query data, more suitable search keywords should be selected to cover different aspects of public migration attention to thus better delineate the difference and characteristic of urban migrant population; second, this paper focus on the panel data analysis; future work will emphasize on the time-series analysis and excavate more information from a dynamic perspective. author contributions: c.l. participated in all phases; j.h. helped in conceiving and designing the research; x.d. helped in paper organization and language correction. all authors have read and approved the final manuscript. migration of skilled workers and innovation: a european perspective rural-urban migration and urbanization in china: evidence from time-series and cross-section analyses interprovincial migration, population redistribution, and regional development in china: and census comparisons chinese floating migrants: rural-urban migrant labourers' intentions to stay or return the elite, the natives, and the outsiders: migration and labor market segmentation in urban china the working and living space of the 'floating population'in china has rural-urban migration promoted the health of chinese migrant workers? increasing internal migration in china from to : institutional versus economic drivers settlement intention characteristics and determinants in floating populations in chinese border cities. sustain fang, f. farmers' rural-to-urban migration, influencing factors and development framework: a case study of sihe village of gansu, china modeling urban spatial expansion considering population migration interaction in ezhou what happens to the health of elderly parents when adult child migration splits households? evidence from rural china does parental migration have negative impact on the growth of left-behind children?-new evidence from longitudinal data in rural china reforming the household registration system: a preliminary glimpse of the blue chop household registration system in shanghai and shenzhen is china abolishing the hukou system? china q relaxation in the chinese hukou system: effects on psychosocial wellbeing of children affected by migration china's permanent and temporary migrants: differentials and changes skilled and less-skilled interregional migration in china: a comparative analysis of spatial patterns and the decision to migrate in - prediction of epidemic spread of the novel coronavirus driven by spring festival transportation in china: a population-based study migration and economic mobility in tanzania: evidence from a tracking survey exploring the changing patterns of china's migration and its determinants using census data of china's floating population and their settlement intention in the cities: beyond the hukou reform economic transition, urbanization and population redistribution in china dynamic population mapping using mobile phone data uncovering patterns of inter-urban trip and spatial interaction from social media check-in data spatial pattern of population daily flow among cities based on ict: a case study of "baidu migration migration patterns in china extracted from mobile positioning data inferring patterns of internal migration from mobile phone call records: evidence from rwanda inferring international and internal migration patterns from twitter data google econometrics and unemployment forecasting predicting initial claims for unemployment benefits do google searches help in nowcasting private consumption? a real-time evidence for the us monitoring influenza epidemics in china with search query from baidu the th china statistical report on internet development hukou and non-hukou migrations in china: comparisons and contrasts determinants of migration intentions in hubei province, china: individual versus family migration study on the predictive and relationship between tourist attractions and the baidu index: a case study of the forbidden city analysis of spatial patterns of public attention on housing prices in chinese cities: a web search engine approach short-term forecasting of japanese tourist inflow to south korea using google trends data data mining from web search queries: a comparison of google trends and baidu index student searching behavior and the web: use of academic resources and google human behavior and the principle of least effort: an introduction to human ecology great expectations? the subjective well-being of rural-urban migrants in china the educational consequences of migration for children in china human migration and health: a case study of the chinese rural-to-urban migrant population house price bubbles in china what determines the settlement intention of rural migrants in china? economic incentives versus sociocultural conditions an analysis of push and pull factors in the migration of rural workers in china a double-pull model of rural labor migration and its in situ urbanizationeffect: cases studies of three coastal areas in southeast china is the push-pull paradigm useful to explain rural-urban migration? a case study in uttarakhand push' versus 'pull' factors in migration outflows and returns: determinants of migration status and spell duration among china's rural population the analysis of economical pulling factors for migrants in beijing, shanghai and guangzhou after reform and opening life satisfaction in urban china: components and determinants labor migration and earnings differences: the case of rural china towards a labour market in china funding: this research was funded by china postdoctoral science foundation, grant number m . the authors declare no conflict of interest. the founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; and in the decision to publish the results. key: cord- -kuwy pbo authors: liu, jiajun; neely, michael; lipman, jeffrey; sime, fekade; roberts, jason a.; kiel, patrick j.; avedissian, sean n.; rhodes, nathaniel j.; scheetz, marc h. title: development of population and bayesian models for applied use in patients receiving cefepime date: - - journal: clin pharmacokinet doi: . /s - - - sha: doc_id: cord_uid: kuwy pbo background and objective: understanding pharmacokinetic disposition of cefepime, a β-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. this study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment. methods: multiple physiologically relevant models were fit to pediatric and adult subject data. to evaluate the final model performance, a withheld group of pediatric patients and two separate adult populations were assessed. results: seventy subjects with a total of cefepime concentrations were included in this study. all adults (n = ) on average weighed . kg and displayed a mean creatinine clearance of . ml/min. all pediatric subjects (n = ) had mean weight and creatinine clearance of . kg and . ml/min, respectively. a covariate-adjusted two-compartment model described the observed concentrations well (population model r( ), . %; bayesian model r( ), . %). in the evaluation subsets, the model performed similarly well (population r( ), . %; bayesian r( ), . %). conclusion: the identified model serves well for population dosing and as a bayesian prior for precision dosing. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. cefepime is a commonly utilized antibiotic for nosocomial infections. rising resistance, manifesting as increased cefepime minimum inhibitory concentrations (mics), has led to more frequent clinical failures [ , ] . to advise clinical outcomes according to mics, the clinical and laboratory standards institute updated the susceptibility breakpoints and then created a category of susceptibledose dependent for mics of and mg/l for enterobacteriaceae spp. [ ] . achieving goal pharmacokinetic exposures to effectively treat these higher mics can require a precision dosing approach. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. cefepime, like other β-lactams, has pharmacodynamic activity governed by 'time-dependent' activity. the fraction of time that the unbound drug concentration exceeds the mic (ft >mic ) for the dosing interval is the pharmacokinetic/pharmacodynamic (pk/pd) efficacy target for cefepime [ ] , and a target of - % has been previously proposed [ ] [ ] [ ] [ ] . for the currently approved cefepime product and combination agents in the pipeline [ , ] , understanding cefepime disposition and variability is crucial to for optimal treatment of patients. as inter-and intra-patient pk variability can impact the achievement of pd goals, understanding the precision of population dosing is important. further, to fully realize precision dosing, individualized models (e.g., bayesian models) are needed. once developed, these models will form the basis for adaptive feedback and control strategies when paired with real-time drug assays. the purpose of this study was to: ( ) develop and evaluate a unified cefepime population pk model for adult and pediatric patients, and ( ) construct an individualized model that can be utilized to deliver precision cefepime dosing. data from four clinical cefepime pk studies representing unique groups of patients were compiled. subject demographics and study methodologies have been previously described [ ] [ ] [ ] [ ] . in brief, populations represented were febrile neutropenic adults with hematologic malignancies [ , ] , those with critical illness [ ] , and children with presumed or documented bacterial infections [ ] . for the two studies that evaluated adults with neutropenic fever, sime et al. prospectively enrolled patients receiving chemotherapy and/or stem cell transplant who subsequently developed febrile neutropenia and were administered maximum doses of cefepime [ ] . a total of cefepime plasma concentrations in presumably steady-state dosing intervals (third, sixth, and ninth) were analyzed for pk target attainment. whited et al. prospectively studied similar patients (n = ) who were admitted to hematology-oncology services and were receiving cefepime at a maximum dosage for febrile neutropenia [ ] . cefepime pk samples were obtained during steady state and analyzed for population parameters. critically ill adults were studied by roberts et al. as a prospective multinational pk study and included patients who received cefepime (only n = were included for model evaluation) [ ] . last, reed et al. characterized cefepime pharmacokinetics in hospitalized pediatric patients (above months of age) who received cefepime as monotherapy for bacterial infections [ ] . for our study, only those who received intravenous cefepime were included for model development. adult (n = ) and partial pediatric (n = ) datasets were utilized for pk model building ( fig. ) [ , ] . model evaluation was performed with other datasets consisting of independent adult (n = , n = ) and pediatric (n = ) patients [ ] [ ] [ ] ] . pediatric patients from reed et al. [ ] were randomized into the model building or the evaluation dataset. all clinical patient-level data included age, weight, and serum creatinine. an estimated creatinine clearance (crcl) was calculated for each patient [ ] . the cockcroft-gault formula (applied to all subjects) served as a standardized descriptor for the elimination rate constant. this study was exempted by the institutional review board at midwestern university chicago college of pharmacy. to construct the base pk models, the nonparametric adaptive grid (npag) algorithm [ , ] within the pmetrics (version . . ) package [ ] for r [ ] was utilized. multiple physiologically relevant, one-and two-compartmental pk models were built and assessed. the one-compartment structural model included an intravenous cefepime dose into and parameterized total cefepime elimination rate constant (k e ) from the central compartment. the two-compartment model included additional parameterizations of intercompartmental transfer constants between central and peripheral compartments (k cp and k pc ). in candidate models, total cefepime elimination was explored according to full renal and partial renal clearance (cl) models [i.e., nonrenal elimination (k e intcpt) and renal elimination descriptor (k e vectorized as a function of glomerular filtration estimates)] [ , ] . assay error was included into the model using a polynomial equation in the form of standard deviation (sd) a unified cefepime population pharmacokinetic model has been developed from adult and pediatric patients and evaluates well in independent populations. when paired with real-time β-lactam assays, a precision dosing approach will optimize drug exposure and improve clinical outcomes. as a function of each observed concentration, y (i.e., sd = c + c · y). observation weighting was performed using gamma (i.e., error = sd · gamma), a multiplicative variance model to account for extra process noise. gamma was initially set at with c and c equal to . and . , respectively. covariate relationships were assessed using the 'pmstep' function in pmetrics by applying stepwise linear regressions (forward selection and backwards elimination) of all covariates on pk parameters. additionally, a priori analyses examined the effect of covariates on cefepime k e , and both weight and crcl were variables considered a priori to have a high potential likelihood to impact cefepime pharmacokinetics ( [ , , ] . weight and crcl were standardized to kg and ml/min, respectively. further, an allometric scaler was applied to standardized weight (i.e., quotient of weight in kg divided by kg raised to the negative . th power) as a covariate adjustment to k e (esm). ultimate model retention was governed according to criteria described below. the best-fit pk and error model was identified by the change in objective function value (ofv) calculated as differences in − log-likelihood, with a reduction of . in ofv corresponding to p < . based on chi-square distribution and one degree of freedom. further, the best-fit model was selected based on the rule of parsimony and the lowest akaike's information criterion scores. goodness of fit of the competing models were evaluated by regression on observed vs. predicted plots, coefficients of determination, and visual predictive checks. predictive performance was assessed using bias and imprecision in both population and individual prediction models. bias was defined as mean weighted prediction error; imprecision was defined as bias-adjusted mean weighted squared prediction error. posterior-predicted cefepime concentrations for each study subject were calculated using individual median bayesian posterior parameter estimates. to evaluate the final adjusted model, the npag algorithm [ , ] was employed to assess the performance with separate data sets (fig. ). the population joint density from the best-fit covariate adjusted model was employed as a bayesian prior for the randomly withheld pediatric data adult data adult data adult data fig. schematic for data sources in model development and evaluation and separate adult data. in the evaluation process, structural model, model parameters, assay error, and observation weighting were unchanged. goodness of fit of the competing models were determined as described above. simulation was performed to examine the exposures predicted by the final model, employing all support points from the population parameter joint density in the final npag analysis [ , ] . each support point was treated as a mean vector surrounded by the population variance-covariance matrix (i.e., covariance equal to the population covariance divided by the total number of support points). for each subject, simulated profiles were created with predicted outputs at . -h intervals. covariate values for each simulated subject were fixed based on arithmetic means of observed weight and crcl for corresponding adult and pediatric populations. semi-parametric monte carlo sampling was performed from the multimodal multivariate distribution of parameters with the parameter space concordant with the npag population analysis results (i.e., best-fit model) [ table s of the esm] [ ] . maximum dosing regimens were simulated for adult and pediatric populations (total n = ): g every h infused over . h and mg/kg every h infused over . h, respectively. protein binding of % (i.e., % free fraction of total cefepime dose) was accounted for in predicting cefepime concentrations [ ] . the pk/pd target of ft >mic ≥ % was utilized across doubling mics of . - mg/l over the first h of cefepime therapy [ ] . estimates are provided from the first h of simulations as timely administration of effective antimicrobial agents is associated with increased survival [ ] . a total of clinically diverse subjects, contributing cefepime concentrations, were included in this study (n = subjects for model development; n = subjects for evaluation) (fig. a total of cefepime observations were available for model development. cefepime concentrations ranged from . to . μg/ml. the base one-and two-compartment models (without covariate adjustment) produced reasonable fits for observed and bayesian posterior-predicted cefepime concentrations (r = . % and . %, respectively), but population estimates were unsatisfactory (r = . % and . %, respectively) ( table ) . weight and crcl displayed relationships with the standard two-compartment model (i.e., base two-compartment model). volume of distribution was associated with weight (p < . ) and ke (total) was associated with crcl (p < . ). after standardizing weight (to kg) without an allometric scaler in the base two-compartment model, fits for both population and bayesian posterior estimates against the observed data improved (r = . % and . %, respectively; ofv change, ). bias and imprecision for bayesian posterior fits were − . and . , respectively. when covariates (i.e., weight to volume of distribution and k e ; crcl to k e ) and the allometric scaler were applied in the two-compartment model, bayesian posteriors fit well (r = . %; fig. right) with low bias and imprecision (− . and . , respectively), and the population pk model produced good fits of the observed cefepime concentrations (r = . %, bias = . , imprecision = . ; fig. left) . the ofv change from the weightadjusted two-compartment model to the final model was significant at − (p < . ) [ table ]. the final model also produced acceptable predicted checks (fig. ) . thus, a two-compartment model with weight and crcl as covariate adjustments and allometric scaling was selected as the final pk model. the population parameter values from the final pk model are summarized in table . structural model and differential equations that define the population pk are listed in the esm. the population parameter value covariance matrix can be found in table . additionally, weighted residual error plots for the best-fit model (fig. s ) and scatter plots for covariates for the base structural model (fig. s ) can be found included in the esm. for the evaluation subset, bayesian priors resulted in reasonably accurate and precise predictions (population r = . %, bayesian r = . %; fig. ). fig. goodness-of-fit plots for best-fit population cefepime pk model (model development) results of the probability of target attainment (pta) analysis are shown in table this study created a population and individual pk model for adult and pediatric patients and can serve as a bayesian prior for precision dosing. when paired with a real-time assay for cefepime, this model allows for precise and accurate predictions of cefepime disposition via adaptive feedback control. in the absence of real-time assays, these cefepime pk parameters facilitate more accurate population-based dosing table population parameter value covariance matrix for the best-fit model strategies. previous work by rhodes et al. has shown an absolute difference of approximately % in survival probability across the continuum of achieving - % ft >mic in adult patients with gram-negative bloodstream infections, thus understanding the dose and re-dosing interval necessary to achieve optimal pk exposures should greatly improve clinical outcomes for patients treated with cefepime [ ] . individualized dosing and therapeutic drug monitoring of β-lactam antibiotics (e.g., cefepime) are critically important to achieving optimal drug exposure (i.e., optimal ft >mic as the pk/pd target) and improving clinical outcomes [ , , ] . precision medicine has been named as a major focus for the national health institute with $ million invested [ ] , yet precision medicine has mostly focused on genomic differences [ , ] . precision dosing is an important facet of precision medicine, and renewed efforts in precision dosing in the real-world setting are being pursued [ ] . cefepime is a highly relevant example. while rigorous reviews and analyses are conducted during the development phase of an antibiotic, dose optimization is far less ideal for the types of patients who ultimately receive the drug. this is highlighted by the fact that although cefepime-associated neurotoxicity is rare, this serious and potentially life-threatening adverse event has been increasingly reported and few strategies exist for optimizing and delivering precision exposures [ , ] . lamoth et al. found that a cefepime trough concentration of ≥ mg/l has a % probability of predicting neurotoxicity [ ] . huwyler et al. identified a similar predictive threshold of > mg/dl (five-fold increased risk for neurologic events) [ ] . in contrast, rhodes et al. found the cut-off of mg/l to be suboptimal [ ] . furthermore, rhodes et al. performed simulations from literature cefepime data and observed a high intercorrelation amongst all pk parameters (i.e., area under the curve at steady state, maximum plasma concentration, and minimum plasma concentration), suggesting that more work is needed to establish the pharmacokinetic/toxicodynamic (pk/td) profile for cefepime. in addition to complications by these less-than-ideal pk/ td data, clinicians are left to treat patients with extreme age differences, organ dysfunction, and comorbid conditions affecting antibiotic pharmacokinetics/pharmacodynamics [ ] . further, a contemporary dose reduction strategy based on estimated renal function (e.g., estimated crcl using the cockcroft-gault formula) is also likely to be confounded in these patients by intrinsic pk variability, such as changes in volume of distribution, and the challenges of accurately estimating the glomerular filtration rate at any point in time, leading to more 'uncertainties' in balancing dose optimization and adverse events [ , ] . these 'real-world' patients are often under-represented, and thus not well understood, from a pk/pd and pk/td standpoint during the drug approval process. bridging to the more typical patients that are clinically treated is important and central to the mission of precision medicine. the findings of this study can be used to guide cefepime dosing in these 'real-world' patients. several other studies have reviewed population cefepime pharmacokinetics. sime [ ] . in our pediatric population, means of cl and elimination half-life were . l/h and . h, respectively. our simulation findings are similar to those of shoji et al. that the maximum pediatric cefepime dosing did not adequately achieve optimal exposure to target higher mics. while the cefepime package labeling recommends maximum dosages of g every h for adult patients with neutropenic fever and mg/kg every h for pediatric patients with pneumonia and/or neutropenic fever, there may be a need to extend these dosing regimens to other populations (in the absence of aforementioned indications) to achieve the best clinical outcomes by optimizing the pk/pd attainment goals [ ] . other studies also performed a simulation for pta with different cefepime regimens and renal functions. tam et al. found that with a pd target of % f t>mic, g every h ( -minute infusion) achieved approximately % pta for mic of mg/l in patients with crcl of ml/min while g every h achieved barely above % pta for an mic of mg/l in the same population [ ] . nicasio et al. also conducted a simulation using a pd target of % f t>mic in the critically ill with varying renal function. the maximum recommended dosage ( g every h) in patients with crcl between and ml/min achieved a pta of . % at an mic of mg/l; however, when the same regimen was infused over . h, the pta achieved was significantly lower [ ] . collectively, these findings suggest that cefepime exposure is highly variable and may be clinically suboptimal in a large number of patients commonly treated with cefepime. these findings support the need for precision dosing and therapeutic drug monitoring for β-lactam antibiotics to reach optimal pk/pd targets given the high variability in drug exposures. our study is not without limitations. although a relatively large and diverse cohort was included in model development and evaluation, we did not specifically assess certain subgroups such as patients with morbid obesity and severe renal dysfunction. these conditions may require patient-specific models. second, many studies to date included 'real-world' patients with various disease sates (e.g., neutropenic fever, renal failure, sepsis); however, all studies were conducted under the research protocol where doses, and administration times were all carefully confirmed. additional efforts will be needed to evaluate model performance in clinical contexts. a unified population model for cefepime in adult and pediatric populations was developed and demonstrated excellent performance on evaluation. current cefepime dosages are often suboptimal, and population variability is high. precision dosing approaches and real-time assays are needed for cefepime to optimize drug exposure and improve clinical outcomes. failure of current 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patients with respiratory tract infections cefepime in intensive care unit patients: validation of a population pharmacokinetic approach and influence of covariables population modeling and monte carlo simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of rifampin in lungs duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock pharmacokinetics-pharmacodynamics of antimicrobial therapy: it's not just for mice anymore therapeutic drug monitoring of the beta-lactam antibiotics: what is the evidence and which patients should we be using it for? the white house. fact sheet: president obama's precision medicine initiative precision medicine: from science to value. health aff (millwood) precision medicine: changing the way we think about healthcare precision dosing: defining the need and approaches to deliver individualized drug dosing in the real-world setting cefepime and risk of seizure in patients not receiving dosage adjustments for kidney impairment characterizing cefepime neurotoxicity: a systematic review high cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function cefepime plasma concentrations and clinical toxicity: a retrospective cohort study an exploratory analysis of the ability of a cefepime trough concentration greater than mg/l to predict neurotoxicity performance of the cockcroft-gault, mdrd, and new ckd-epi formulas in relation to gfr, age, and body size population pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically ill patients with ventilator-associated pneumonia population pharmacokinetic assessment and pharmacodynamic implications of pediatric cefepime dosing for susceptible-dose-dependent organisms pharmacokinetics and pharmacodynamics of cefepime in patients with various degrees of renal function acknowledgements j.a. roberts would like to acknowledge funding key: cord- -lmnccks authors: bulbul, ozlem; pakstis, andrew j.; soundararajan, usha; gurkan, cemal; brissenden, jane e.; roscoe, janet m.; evsanaa, baigalmaa; togtokh, ariunaa; paschou, peristera; grigorenko, elena l.; gurwitz, david; wootton, sharon; lagace, robert; chang, joseph; speed, william c.; kidd, kenneth k. title: ancestry inference of population samples using microhaplotypes date: - - journal: int j legal med doi: . /s - - - sha: doc_id: cord_uid: lmnccks microhaplotypes have become a new type of forensic marker with a great ability to identify and deconvolute mixtures because massively parallel sequencing (mps) allows the alleles (haplotypes) of the multi-snp loci to be determined directly for an individual. as originally defined, a microhaplotype locus is a short segment of dna with two or more snps defining three or more haplotypes. the length is short enough, less than about bp, that the read length of current mps technology can produce a phase-known sequence of each chromosome of an individual. as part of the discovery phase of our studies, data on microhaplotype loci with estimates of haplotype frequency data on populations have been published. to provide a better picture of global allele frequency variation, we have now tested more populations for of the microhaplotype loci from among those with higher levels of inter-population gene frequency variation, including loci not previously published. these loci provide clear distinctions among biogeographic regions and provide some information distinguishing up to clusters of populations. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. microhaplotypes have great ability to identify and deconvolute mixtures because massively parallel sequencing (mps) allows the alleles (haplotypes) of the multi-snp loci to be determined directly for an individual [ ] . by [ ] , our interest in use of haplotypes focused on very short bmicrohaplotypes.^we have subsequently published on our developing set of microhaplotypes and the criteria for selecting the most useful microhaplotypes for mixture electronic supplementary material the online version of this article (https://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. resolution [ ] [ ] [ ] . as originally defined, a microhaplotype locus (short form, microhap) is a short segment of dna with two or more snps defining three or more haplotypes at reasonable frequencies in a large part of the world. the loci are designed to be typed with mps, which can determine, for sequences of up to about bp, the specific combination of snp alleles on each of the parental chromosomes of an individual. thus, mps provides phase-known data, in contrast to conventional sanger sequencing, at any locus with two or more heterozygous snps. microhaplotype loci have several desirable characteristics including, by definition, multiple alleles. although most microhaps have fewer alleles than most short tandem repeat polymorphisms (strps), microhaps have the advantages over strps of very low mutation rates, absence of stutter, and the ability to multiplex large numbers of loci. sets of microhaplotype loci can be optimized to be useful for individual identification, determining biological relationships, providing information on particular phenotypes, providing information on biogeographic ancestry, or, as noted above, deconvolution of a mixture. knowing the haplotype frequency variation around the world is important in determining how useful particular microhaplotypes will be for any one of those five uses in any specific population. thus, it is important that multiple loci be characterized on as many populations as possible from as many regions of the world as possible. we recently published on microhaplotypes that we have identified and have characterized in populations from around the world [ ] . in that paper, we noted the many ways that microhaps can be used but emphasized the value of microhaps for mixture deconvolution. to expand global characterization, we have now collected and analyzed new data on individuals for snps that define microhaplotypes in additional populations, bringing the total from to populations for microhaplotypes. with this broader geographic representation, we now are considering how well microhaps provide information on biogeographic ancestry. table s . the populations in the table are organized by geographic region. the table also includes the three-character abbreviations used in illustrations, and the unique sample identifier (uid) in the alfred database <https://alfred.med.yale.edu> [ , ] for the description of each sample. the new population samples had only small amounts of dna available and were chosen, in part, to provide somewhat more uniform sampling of populations around the world. all samples were collected with full informed consent per local law allowing studies such as this. to characterize the additional populations and emphasize ancestry inference, we chose loci with higher ranks by informativeness (i n) based on the populations already evaluated for all microhaplotypes and additional loci from among those loci subsequently characterized [ ] . eight loci not previously published are noted in table . availability of taqman assays already on hand in the laboratory determined which loci were specifically tested first. the current set of loci involves snps and represents an empiric balance of available assays and sufficient dna. additional loci may be tested on some of these populations in the future, but the available dna has been exhausted for several of these bnew^populations. all markers were typed using taqman assays obtained from thermo fisher. the individuals with large amounts of dna were typed following manufacturer's protocols with reaction volumes reduced to μl, run in -well plates, and read on an ab ht using applied biosystems' sds (sequence detection system) software. to maximize the number of snps that could be typed on the small amounts of dna available, a preamplification protocol was employed as described [ ] . the haplotypes were estimated using phase version . . . [ , ] as described previously [ ] . this approach provides good allele frequency estimates for these reference populations. the effective number of alleles, a e , was calculated following kidd and speed [ ] . informativeness, i n , was calculated using the formula of rosenberg et al. [ ] . structure analyses [ ] were done for the full set of populations and loci with independent runs at each k value. pca was calculated with addinsoft's xlstat . table lists the previously unpublished loci and their definitions using the nomenclature for microhaplotypes we previously proposed [ ] . the definitions of all loci, including those previously published, are in alfred <alfred.med.yale. edu>. the allele frequencies for all loci, including the new loci, are now in alfred for all populations along with the data on the rest of the original microhaps [ ] . data on all these loci can be retrieved using the key word microhap on the alfred home page or on the drop down search menu. table lists all microhaplotypes along with their a e and i n values, with the ranks from largest to smallest, using all populations to calculate the statistics. figure is a scatterplot of the loci by these two statistics. comparison of the scatterplot in fig. with that in [ ] shows that these loci have proportionately fewer loci with i n less than . and a e less than . . figure presents scatterplots from the principal components analysis (pca) of the populations based on their allele frequencies at the loci. the first two pcs account for % of the variation (fig. a) ; the major continental regions--africa, southwest asia, europe, south central asia, east asia, americas, and pacific-clearly separate from one another. figure b shows an enlarged view of the tighter cluster of populations with labels for the individual populations following the labels in supplemental table s . the third pc accounts for an additional . % (fig. c ) and separates the native american populations more distinctly from the east asian populations. the fourth pc (not shown) accounts for only an additional % of the variation and moves the pacific island populations away from east asia. figure shows population averages for structure analyses at k = and k = . at k = , except for small amounts of bnoise,^the majority of africans are assigned to a single cluster. the majority of east asians are assigned to a single cluster, and the majority of the native americans are assigned to a single cluster. three of the bamericas^populations from the genomes project [ ] are highly admixed in these analyses and are labeled as such. at k = , the populations farthest north (eastern siberia, mongolia) in east asia cluster together apart from other east asians while the sub-saharan african populations subdivide into distinctive patterns for west africa compared to central and east african populations. comparison of the structure results at k = with fig. b shows, by the two distinct statistics, that information on the finer relationships is present in the dataset. forensic questions that can be addressed by microhaps include resolution of mixtures, identifying relatives, inferring ancestral origins, estimating phenotype, and individualization. in this study, we have emphasized ancestral origins, but we note that this set of microhaplotypes spread across human autosomes can be very useful for mixture deconvolution, familial inference, and individualization as well. microhaplotypes can incorporate snps useful for estimating aspects of phenotype, but we have not considered that type of information. our analyses of these loci have focused on biogeographic ancestry. in future papers, we will present analyses of random match probabilities (rmp) and familial inference for sets of microhaps. we note that we have estimated the rmp for the reference ceu population sample table for these loci; the estimated rmp is between − and − . these loci have different characteristics as measured by a e and i n . those differences are shown in fig. . we note that the two microhaps with the highest i n values (mh kk- and mh kk- ) are among the loci with the lowest a e values (ranks and , respectively, table ). examination of the haplotype frequencies shows that the global patterns are noticeably different and have large regions of the world with one haplotype at greater than % frequencies, albeit different haplotypes in different regions (supplemental fig. ) . the other six loci with i n > . show a range of a e values from nearly three to nearly six. basically, these loci have multiple alleles everywhere but very different allele frequencies. we also note that some of the loci have low ranks for both measures. the pca in fig. shows that this set of microhaps distinguish among populations from some of the different biogeographic regions. africa and the americas are very clearly distinct. the eastern and northern of the eurasian populations also fall into a loose cluster clearly distinct from european populations. what is interesting is how relatively close the european populations cluster in this global set of populations. on the other hand, this is not surprising because europe is a geographically small area. figure b makes the global dispersion is reflected in the structure results in fig. . at k= , there are quite distinct biogeographic regions with intermediate populations showing partial assignment to flanking clusters. europe and southwest asia are the exception in that a southwest to northeast cline of two clusters is seen. this is a pattern that has been seen with many sets of ancestry markers [e.g., , ] . our previous paper studying loci on populations [ ] had loci with a e > . giving a very high probability of identifying and resolving a mixture of two individuals; the current dataset has loci in this range. by definition, these loci have multiple alleles and relatively low frequencies for each of the alleles. these same attributes make these good for identifying relatives and make the likelihood of two unrelated individuals having the same multi-locus genotype vanishingly small. three of the new microhaps are in the region of slc a . the coding snp at slc a that is associated with skin color, rs , is located on chromosome at nt , , (build ) and shows a different global pattern of variation from even the closest of these three microhaps which is kb away. the three microhaps also differ in their global patterns (supplemental fig. ). at this stage, we are not choosing which is better since the different microhaps may differ in appropriateness for different purposes. the global variation is not identical, with i n values from a high of . (rank ) for mh kk- to . (rank ) for mh kk- . in the context of loci with multiple alleles, including all three will have little effect other than strengthening whatever pattern in structure analyses is favored by that chromosomal region--europe and sw asia are distinct from east asia. the addition of populations and emphasis on microhaplotype loci with higher i n values on average, compared to the microhaps in [ ] , has shown that these loci constitute a significant panel for ancestry inference. these results provide additional material for selecting panels of microhaplotypes optimized for different purposes. that many of the loci also have high a e values argues that most of these loci have value for mixture deconvolution. the overall results support our previous findings [ ] that many microhaplotypes have use for both ancestry inference and mixture deconvolution. the markers with a e > . are particularly good at mixture deconvolution, and the same logic indicates they will be very useful for familial relationships and individualization. as we have been able to identify and characterize more microhaplotypes as part of our discovery phase, it has become possible to begin the laboratory studies to determine which loci will be the most robust with actual mps typing. our objective has been to identify and characterize a large number of loci with useful statistical characteristics such that molecular issues that may exclude some loci from mps multiplexes will leave sufficient loci. these studies provide the necessary estimates of reference population allele frequencies. when actual multiplex kits are available, the identification of microhaplotype genotypes in individuals using mps promises to be an important adjunct to forensic casework. evaluating microhaplotypes across a global set of populations microhaplotype loci are a powerful new type of forensic marker current sequencing technology makes microhaplotypes a powerful new type of genetic marker for forensics genetic markers for massively parallel sequencing in forensics criteria for selecting microhaplotypes: mixture detection and deconvolution alfred: an allele frequency resource for research and teaching alfred: an allele frequency database for anthropology mongolians in the genetic landscape of central asia: exploring the genetic relations among mongolians and other world populations a new statistical method for haplotype reconstruction from population data accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation informativeness of genetic markers for inference of ancestry inference of population structure using multilocus genotype data proposed nomenclature for microhaplotypes a global reference for human genetic variation evaluating a subset of ancestry informative snps for discriminating among southwest asian and circum-mediterranean populations increasing the reference populations for the aisnp panel: the need and benefits key: cord- - ggxz authors: bocquet-appel, jean-pierre title: explaining the neolithic demographic transition date: journal: the neolithic demographic transition and its consequences doi: . / - - - - _ sha: doc_id: cord_uid: ggxz three main questions are raised in this chapter. . the part of the signal of the ndt which is demographically identifiable, based on the proportion of the immature skeletons in cemeteries, shows that a baby-boom occurred and, beyond that, with the onset of the change in the economic system, a fertility transition towards high values also occurred. what was the biodemographic cause of this fertility explosion, beyond the proxy variable represented by sedentarism? the cause is a major shift in the maternal energetics of farming communities relative to mobile foragers. in the energy balance there was (i) on the intake side, an underlying trend towards a reduction in low-calorie food from hunting and fishing, and a correlative increase in high-calorie food from agriculture, (ii) on the expenditure side, a reduction in the physical energy devoted to mobility and the maternal stress of child transportation. . the ndt is detectable from a signal representing a fertility transition, but the transition relating to mortality is missing and must be inferred. if, during the fertility transition, mortality had remained the same as in the preceding forager period, then the population would have grown infinitely. the assumption of unchanged mortality during the entire fertility transition is therefore not realistic. mortality, in its turn, must have begun to rise well before the end of the fertility transition. but when? why? one of the answers consists of a model where, except at the start of the process, birth and mortality rates rise more or less simultaneously, bringing about a typical rate of increase for pre-industrial populations of slightly above zero. . according to the level and speed of the population growth, what should we expect in terms of population structure? what are the expected effects of this growth, not only on the population in numbers but also on age distribution, the distribution and structure of families, the distribution of households and on family systems? the signal of a major demographic shift during the transition from forager-horticulturists to farmers in europe, north africa and north america was detected in palaeoanthropological data from more than cemeteries. this signal, which is characterised by a relatively abrupt increase in the proportion of immature skeletons, has been named the neolithic demographic transition (ndt) (bocquet-appel and naji , bocquet-appel , bocquet-appel and paz de miguel ibanez . the demographically identifiable part of the signal indicates a sharp increase in the birth rate, and beyond, a transition towards higher fertility values than those characterising the preceding forager period. this ndt raises a number of questions, starting with the cause of the increase in fertility. because of its overall impact on the fertility of populations that turned to farming, wherever they were located on the planet, we would expect one or more identical causes having a determining effect on the variability of fertility, which should contribute to their identification. assumption number one, which was formulated a long time ago, is the impact of sedentism on fertility in nomadic forager populations (lee b , binford and chasko , sussman , binford , carr-saunders , malthus . although this is a broad assumption, it tends to be borne out by the few data we have on nomadic populations in the process of sedentism (binford and chasko , romaniuk , roth , roth and ray , which are outlined below. the same applies to archaeological data representing the cemeteries of forager and farming populations, whose putative gradient of mobility from nomadic to sedentary (see below) closely coincides with the expected birth rate estimates. however, this broad assumption is a proxy variable for other underlying biodemographic variables that come into play. which are these? in this chapter, the model of the relative metabolic hypothesis (for a summary see valeggia and ellison ) , which is used in order to integrate the physical constraints of mobility, breastfeeding and maternal nutrition, is set forth to explain the variation in fertility during the ndt. the second question raised by the ndt concerns its scenario. the ndt is detectable from a signal representing a shift towards higher fertility values, but the mortality part of the signal is missing and must be inferred. it is as if, in the contemporary demographic transition (cdt), only the profile representing the drop in birth rate was known, so that the drop in mortality would have to be estimated from this. the contemporary transition has multiplied the world's population by six in years. so what should be done? in order to build up the scenario of the ndt, we need a model. the universal density-dependent (or homeostatic) demographic model is used. from an updated sample of old and new world cemeteries in the northern hemisphere ( cemeteries; see fig. ), a birth rate estimate is obtained ranging from . to . per , over years during the neolithic fertility transition (see below). if, during the fertility transition, mortality had remained the same as in the preceding forager period (≤ . per ), then the population would have reached an unrealistic number. the assumption of unchanged mortality throughout the fertility transition is therefore unrealistic. mortality must have increased in turn well before the end of the fertility transition. but when and why did this happen? what timing for birth and mortality rates should we put in the ndt scenario? how should this scenario be tested, and with what data? the third question, which follows on from the model of the ndt, concerns the impact of population growth on the population itself and its cultural expression. what were the effects of this growth, not only on population numbers but also on the various aspects of its evolving structure such as age distribution, the distribution and composition of families, the distribution of households, family systems (extended or nuclear) and the institutions developed to regulate tensions between groups/individuals in a steadily growing population? in the first part on "experimental demographics", the model of the relative metabolic load is tested with an ethnographic sample of populations of western north american indians (jorgensen (jorgensen , . in the second part, we explore a model of the ndt where birth rate and mortality evolve in tandem, producing a growth rate slightly above zero. in the third part, the effects of this demographic growth on the population structure are briefly reviewed. thirty years ago, the archaeologists and anthropological demographers binford and chasko ( ) detected what they called the "first major demographic transition" and which, in this volume, is called the ndt. they correctly identify its major cause -fertility and not mortality -along with its starting point at the end of pleistocene. the fascinating aspect of this discovery, which did not receive the coverage it deserved, is that the demographic data on which it rests are very far removed, historically and ecologically, from neolithic data, since they relate to the nunamiut eskimos of central north alaska. more interesting still is that, in the space of a single generation, from to , the nunamiut -who became sedentary at the same time as other geographically close indian populations (athapascan: roth , james bay cree: romaniuk ) -successively experienced the explosive fertility of the ndt, followed by a collapse with the advent of the contraceptive practices of the cdt. the same is true of neighbouring populations. binford and chasko explore several avenues in attempting to account for this fertility explosion, from variations in coital frequency with the mobility of hunters to a dietary shift. they detect an influence of cereal consumption on fertility (fig. ) and conclude that this first demographic transition would have been a by-product of sedentarism and its impact on diet and the division of labour. to these ethnographic data can be added palaeoanthropological data from cemeteries, which, although cannot be used to test the biodemographic assumption, do make it possible to test the proxy assumption of sedentism. table gives the values of the non-conventional demographic indicator p for a set of nearly , skeletons from cemeteries worldwide (guerrero et al. this volume, bocquet-appel and naji , bocquet-appel ) , which are divided into three mobility groups as indicated by archaeologists: nomadic (foragers), semi-sedentary (shellmidden foragers) and sedentary (farmers). a further breakdown of mobility is not fig. correlation between quantities of imported cereals and the general fertility rate among nunamiut eskimos . note: from binford and chasko ( , table gives the result of the validation test for the null hypothesis positing no difference in the p proportion between paired groups. the difference is significant between the two most different mobility groups, i.e. hunter-gatherers (mobile) vs. farmers (sedentary) (p = . ), with a lower indicator of expected birth rate in hunter-gatherers than in farmers, but it is not significant between the intermediate group of foragers (semi-sedentary) and each of the two other preceding groups. this test underlines, first, that not only the expected gradient of birth rate with mobility has been well observed in the archaeological data, but also the ambiguity of the demographic response of the intermediate semi-sedentary group attributed to the shellmidden foragers of the literature. this ambiguity is definitely accounted for by the test of relative metabolic load with the ethnographic data given below (see table ). fertility remains uniformly low with a low-calorie diet of aquatic animals (fish and some shellfish), but rises when the energy constraint of mobility decreases. table fitting models (ols) of demographic density (proxy for fertility) by the impact of diet b (energy intake) and mobility b (energy expenditure). in rows: diet category. figure provides d and d graphical representations of the data and the corresponding adjusted planes p > |t|: * ≤ . , * * ≤ . , * * * ≤ . , * * * * ≤ . taking a different angle, anthropological demographers and reproduction biologists are trying to understand the determinants of natural female fertility. let us recall that for a fixed reproductive duration of roughly years, the fertility level can be expressed by the duration of the birth interval. during the fertile life of a mother, when the duration of the birth interval increases, the number of children born decreases. the duration of the birth interval is inversely proportional to fertility. but the inter-population variation of the birth interval is large (wood ). in the context of the shift to agriculture, three main assumptions can account for this variation in the birth interval. the first is maternal stress from transporting children, caused by the forager mother's inability to care for more than one dependent offspring at a time (blurton jones , blurton jones and sibly , binford , sussman , lee a bleek ) . the duration of the birth interval is a function of the distance covered by a mother and of the growing weight of a child. this assumption has produced contradictory results (roth vitzthum ) . the second assumption postulates (i) that the duration of the birth interval is an (inverse) function of the intensity and frequency of suckling (konner and worthman , wood et al. , diaz , lewis et al. , peng et al. ) and (ii) that suckling during the transportation of children by their mothers decreases during the transition on the mobility gradient from nomadic foragers to sedentary farmers (bocquet-appel and naji , lee , sussman . but several studies have shown no correlation between the intensity of suckling and the return of the reproductive cycle (fink et al. , worthman et al. , tay et al. . the third assumption is the relative metabolic hypothesis for maternal nutrition (huffman et al. , lunn et al. , ellison et al. , ellison , valeggia and ellison . the duration of the birth interval is an (inverse) function of the energy balance (energy status and energy balance). the energy balance is determined by energy expenditure (on necessary milk production and physical activity) and postpartum energy intake (mother's diet). curiously, interpretations of the field data have been possible sometimes thanks to one of the assumptions, and sometimes to the other. but a recent study has produced a major advance in favour of the relative metabolic load model. in breast-feeding women with natural fertility, the date of resumption of the cycle is determined by a positive return of the relative energy balance after childbirth and its stability for a period of about - months (valeggia and ellison ) , the whole determining the duration of postpartum amenorrhea. in the remainder of this chapter, the variable representing the positive return of the relative energy balance (eb) is written as Δ t e b + e, with the index t indicating the positive return at time t after childbirth and e the stable duration of eb positive, ending with the return of the menses. without additional studies, the stable duration of eb positive cannot be regarded as invariant between populations. the duration of postpartum amenorrhea is equal to t + e. the suckling frequency is a necessary but not sufficient signal determining the duration of postpartum amenorrhea. to this duration, in an anthropological context, we need to add the postpartum sex taboo, c, determined for cultural reasons. the whole gives the birth interval t+e+c. in ethnographic populations, the average duration of the postpartum taboo is shorter among mobile foragers than among sedentary farmers (see table , saucier ). valeggia and ellison's data and their interpretation by their relative metabolic load model make it possible to take into account the intensity of suckling frequency and the maternal energetics required to ensure reproduction, in a given economic and ecological context. this in turn makes it possible to understand the reasons for the diversity of interpretations of the survey data, which sometimes control one variable and sometimes another. in the context of the shift from a forager to a farming economy, if the cursor for suckling frequency (high), energy status (regular in the context) and the postpartum sex taboo is kept fixed, we would expect input and output in the energy balance to be affected by -a reduction on the input side in the proportion of low-calorie food items (tissues from hunted animals and fish) relative to high-calorie food items (wheat, lentils, peas, maize); -a reduction on the output side in energy expenditure among foragers, via reduced physical activity involved in mobility and the maternal stress of child transportation. this double effect on the energy balance results in a shorter duration of postpartum amenorrhea (t + e), and thus to increased fertility. the fertility model determined by the relative metabolic load is represented in fig. . we notice that its demographic effect is similar for sedentary populations using high-calorie food items, whether these are farmers or foragers such as the natufians in the levant (fig. : position "+" on the horizontal axis of the energy intake and "−" on the vertical axis of the energy expenditure). the predictions of this fertility model are tested with the data for the ethnographic populations of jorgensen's western north american indian sample on their first european contact ( , ) . these data provide information on the density of consumed calorific energy, via the percentages of diet items (hunting, aquatic animals, agricultural produce) and physical activity, via a graduation of mobility (from nomadic, coded " ", to sedentary coded " "). information is thus given on demographic density (per mile ), but none on fertility or the postpartum sex taboo. to test the fertility model with these data, two assumptions must be made. the first relates to the use of demographic density as a proxy variable for fertility. if the demographic regime of populations (determined by their inputs and outputs: birth rate, mortality and migration in and out) has not been disturbed in the recent past, their demographic densities will therefore mainly reflect their fertility. there are two main causes of disturbance: (i) a variation in demographic density due to migratory movements (in or out), as in the contemporary examples of rural migration and concentration in megalopolises across the entire planet, and (ii) an abrupt negative or positive variation in the fertility of a population, but where the current demographic density is a reflection of its former fertility: an example is the chinese population today, with its high demographic density and very low fertility. the assumption of an absence of major disturbance in the demographic regimes of the ethnographic sample prior to the first european contact seems acceptable. the second assumption relates to the postpartum taboo, whose duration is not indicated in the ethnographic data and which we might be tempted to regard as a random variable, independent of the demographic density. as seen above, it is not. average postpartum duration (c) is longer in the relatively high-density populations of sedentary farmers than in mobile foragers. paradoxically, when demographic density rises in these data, we should expect an undervaluation of fertility energetics. this will be looked into below. the impact of mobility and diet on demographic density, used as a proxy variable for fertility, is tested by means of simple linear adjustments (ols), z = b + b x + b y + h, with x, y, b and h, respectively, representing, for energy intake, the proportion of a specific food (from hunting, aquatic animals and agricultural produce), for energy expenditure mobility, regression coefficients and an uncontrolled residue. the d and d representations of the models are given in fig. . a successive examination of the three diet categories (table ) shows the following: -with energy intake from hunting (table , line , fig. a ), i.e. from low-calorie food items, only energy expenditure (mobility) has a significant influence on fertility, which rises when energy expenditure decreases; -with energy intake from aquatic animals (mainly fish and some shellfish, table , line , fig. b) , there are two significant influences: a relatively weak negative influence of low-calorie food items and a strong influence of energy expenditure (mobility). fertility rises when the low-calorie food items and the energy expenditure both decrease. -with energy intake from farming produce (mainly maize, table , line , fig. c ), the influences of energy expenditure and energy intake from high-calorie food items are both significant. fertility increases more when, simultaneously, energy intake from high-calorie food items increases and energy expenditure decreases, with energy intake exerting a more perceptible influence than energy expenditure. allowing for a probable undervaluation of the fertility energetics in the ethnographic data when the demographic density rises due to the impact of the postpartum taboo as discussed above, the slopes of the adjusted planes in the graphs (fig. ) should be tilted a little more towards demographic density. to summarise, the relationships observed in the ethnographic data between the variables representing the relative metabolic load and demographic density, used as a proxy for fertility, all take the directions predicted by the fertility model. this is the message contained fig. d representation of demographic density (proxy for fertility), accounted for by energy expenditure (mobility, from = nomadic to = sedentary) and energy intake (diet from (a) hunting, (b) aquatic animals, (c) agricultural produce) with the relative metabolic load model applied to jorgensen's sample ( jorgensen's sample ( , of western north american indians on first european contact. a d representation of demographic density is given at the top of each graph. the statistical tests are given in table fig. profile of variation in the levant, in the relative chronology dt, in (top) the demographic indicator p and (bottom) the proportion of gazelles in animal remains (two smoothers, dwls, the smoothest, and loess, the least smooth; same parameters alpha = . ; from guerrero et al., this volume) in the ethnographic data, which should help us to gain a better understanding of the cause of the ndt. the interpretation of the p profile of the ndt at the source of agricultural invention in the levant can thus be taken further. along with the increase in fertility, the signal of the ndt expresses a steady reduction in the duration of the reproductive cycle and, beyond this, of the positive return of the relative metabolic load. this reduction must have been determined relatively to the forager society, simultaneously by an energy intake comprising a decreasing proportion of low-calorie food items (hunting) and an increasing proportion of high-calorie food items (cultigens), as well as a reduction in energy expenditure accompanying sedentarisation. figure represents the profiles for the fertility transition in relative chronology (dt) and for hunting (guerrero et al. this volume) . these profiles show a negative correlation: when the share of hunting in the diet increases, fertility decreases, and vice versa. this is rather remarkable since the phenomenon covers two periods of increasing fertility/decreasing hunting (at − dt and dt). the coincidence of hunting profiles and demographic profiles in the levant, over a relatively long duration, has already been noted (guerrero et al. this volume) . the fertility model can provide at least three explanations for the parallel direction of these profiles, one in terms of a reduction in energy expenditure, via reduced mobility, another in terms of a reduction in the proportion of low-calorie food items (represented by gazelles) with a probable correlative increase in high-calorie food items (represented by wheat, lentils and peas) or a combination of both. this last explanation seems the most likely. with regard to the reduction in energy expenditure, this certainly relates to the transportation of children. but with the growth of the population, the number of families, of individuals within families and of extended families also increases. this increase in average family size and in the number of extended families points to a probable supply of surrogate carers for the mothers, i.e. to more collective responsibility for taking on the physical constraints of motherhood and domestic activities during the nursing period, which causes a further increase in fertility. as for other animals, demographic growth in human populations is regulated by density-dependent mechanisms (reher and ortega osona , lee , blum, bonneuil and blanchet ; for a discussion, see wilson and airey ; for mammalians, see sibly, hone and clutton-brock ) . any significant variation, due to a disturbance, from the long-term average value of the birth rate (b) or mortality rate (d) will quickly return to near this average value. the difference between the birth and mortality rates corresponds to a population where demographic growth (r) is close to zero (b − d = r ∼ = ). it is said of such a population that it is in homeostatic equilibrium or that it fits the density-dependent model. if density-dependent regulation were absent, then any reduction in the population's growth rate could end in extinction, while any increase could lead to an infinitely expanding population (sibly, hone and clutton-brock ) . this density-dependent pattern has been detected in the archaeological data representing the increase in site density in peru (bandy ) . the near-zero value of the long-term growth rate of prehistoric populations is generally agreed upon (hayden , hassan , dumond boone countered) and is verified in the archaeological data (bocquet-appel, demars, noiret and dobrowsky ) . a remarkable and well-documented fact in human demographic history is the response of the metapopulation to the major disturbance represented by the cdt. across the planet as a whole, this transition has raised life expectancy at birth from to years and lowered the average number of children per woman (tfr) from to or less in just three centuries. against the backdrop of the density-dependent model, the cdt has to be seen as a very large-scale disturbance with intrinsic causes (see below), whose return time to homeostatic equilibrium towards a zero growth rate in the endogenous geographical zones of invention was proportional to the scale of the disturbance. this transition lasted nearly years in the uk and years in denmark. it must be remembered that the scenario of the cdt was a transition towards lower mortality, followed by a transition towards lower fertility (fig. ) . the pattern of this global transition is therefore, in fact, of two superimposed transitions that vary together, with a greater or lesser time-lag. the cdt is the only known historical reference pattern of a major demographic shift (other than induced by a catastrophe) representing a demographic transition. it is therefore legitimate to compare these two transitions, the ndt and the cdt, which, in terms of the scale of their impact on human evolution, are of the same order. first of all, as indicated above, compared to the cdt, only the fertility transition profile for the ndt is observed from cemeteries data, but the mortality transition is missing. we then see that the direction of the fertility transition is reversed, tending towards higher values for the ndt and lower values for the cdt. this reversal has led me to formulate the assumption of an ndt pattern that is a mirror image of the contemporary transition, both in the order of the demographic variables (b followed by d in the ndt, and not d followed by b as in the cdt) and in their directions (transitions towards increasing and not decreasing values). therefore, the scenario begins as follows: for reasons due to the demographic densification of the foragers' world (cohen ) , which determined ecological pockets of sedentism in eurasia at the end of pleistocene and in mesoamerica around bp, the transition towards an increase in fertility would have begun, followed by a mortality transition towards these same high values, for the reasons of homeostatic equilibrium indicated above. the important question is the tempo of this return to equilibrium, during which there would have been an appreciable growth in the population. figure represents the profiles of the fertility transition in the ndt observed in sites in the northern hemisphere (no levantine sites). from the relationship between p and the birth rate given by the estimators of the pre-industrial model (bocquet-appel ) , life expectancy at birth, average number of children (tfr) and females surviving to mean childbearing age can be estimated using the assumption of a stationary population, for example with coale's chart ( : ) . this chart uses the different relationships between tfr, nrr and a growth rate set at zero (hinde : , pressat . table gives the values of these different demographic variables on the average profiles ( p ) of the fertility transition in the northern hemisphere (fig. ) , at dt = , marking the onset of the ndt, and at dt = , the first plateau of the p profile marking the end of the transition. the estimated birth rate is . per at dt = and . per at dt = . the large differential of the two values indicates that the return to the equilibrium could not occur at the end of the fertility transition, otherwise the number of humans would have become unrealistically enormous. to reconcile a birth rate (fertility) that rises slowly but continuously for years with a realistic growth rate slightly above zero (about . %), which is typical of pre-industrial populations, mortality must table estimated values for different demographic parameters using coale's relationship ( : ) , starting from the birth rate estimate given as input data using the paleodemographic estimators ( p ) for the pre-industrial model (bocquet-appel ) ( ) birth rate per . ( ) total fertility rate (births per female). ( ) life expectancy at birth. ( ) females surviving to mean childbearing age (%). model of the neolithic demographic transition. in this model, a fertility transition towards higher values (in black), driven by sedentism, appears at the onset of the new economic system, at dt = . but a mortality transition soon follows, also towards higher values (grey), driven by the density of village life and contamination (drinking water, latrines) associated with zoonoses, as well as by a change in nursing patterns. in a similar model published by coale ( ) , the two transitions are reversed compared to the model presented here rise at approximately the same rate. this model is shown in fig. . at this rate of increase, the population doubles in years. in this model (fig. ) , the birth rate (and fertility) rises continuously, determined by the age pyramid and age-specific fertility rates, which (with the tfr) increase as a result of a shift in maternal energetics. with the growth of the population, the number of surrogate carers also increases (grandparents, older children), which may have helped to increase fertility. the maximum stable birth rate ( per ) may have been reached when, in the farming system, maternal energy expenditure on physical activities fell to a minimum as it became integrated into the overall workings of the social system, while energy intake rose to a maximum through the incorporation, thanks to regular and stable supplies, of the high-calorie food items now being selected. with sedentary village life and the corresponding growth in local population density, mortality rates inherited from the foragers eventually rise, particularly in children under years of age. causes of increased infant mortality would include lack of drinking water supplies, contamination by faeces and the absence of latrines, as well as reduced breastfeeding. the susceptibility of humans to new infectious diseases results from complex factors such as modified exposure to animals, microbial adaptation, nutritional status and density of the host population. the high proportion of children in neolithic burial sites could have resulted from the emergence of highly virulent zoonoses that were newly acquired. interestingly, however, it can be seen that the variation in the proportion of skeletons aged - years in cemeteries, set within the frame of the relative chronology dt, mimics the proportion of -to -year-olds, in spite of the taphonomic impact (see fig. ). this role of infectious diseases in the homeostasis of population growth is still mainly hypothetical. molecular analyses of the divergence between related animal germs are only an indirect way of assessing their period of acquisition by humans. candidate germs by "epidemiological inference" from current pre-industrialised areas and those with poor health facilities should include germs associated with animal domestication, such as paramyxovirus (measles), poxvirus (smallpox), rotavirus and coronavirus (diarrhoea, one of the main killers of children under years of age), streptococcus (including streptococcus agalactiae, linked to cattle milking) or staphylococcus. some germs believed to co-evolve with humans should also be studied, such as plasmodium (p. falciparum, and p. vivax, which is believed to have emerged more recently) or herpesvirus. but only diseases involving a haematogenic process will be easily detected. research in molecular anthropology should provide information in this promising area (mira, pusker and rodriguez-valera ) . during the ndt, the population may have lost several years of life expectancy. finally, mortality stops rising once the regional density and concentration of the population have stabilised. a model of a neolithic transition, graphically resembling of the one in fig. , has been published by coale ( ) but, contrary to the model put forward here, "the death rate increased as a result of greater susceptibility to disease in village life, and perhaps also because agriculture is vulnerable to climatic crises. if the death rate did increase, then it is certain that the birth rate also rose, and by a slightly greater margin" (coale: ) . in coale's model, the increase in the birth rate does not have any explicit cause other than homeostasis. this question as to which variable, the birth rate or the mortality rate, initiated the ndt is not a chicken-and-egg problem. the idea that demographic growth in the neolithic, which was without historical precedent, could have been triggered by an increase in mortality is bizarre. to sustain a village life, the population had to reach a certain number and this number could only be achieved through an increase in fertility. rising mortality, as the population density increased, could only come after, and not before, the initial population growth. seeing an increase in mortality as triggering demographic growth is like starting off a race by making the runner shoot herself in the foot: she will not run far. but coale has correctly thought out the constraint weighing on the increase in these rates: they must follow each other closely for the growth rate to remain viable. during the ndt, with the tempo at dt = years (fig. ) , although fertility increased considerably (the estimated tfr increased from . to . children per woman), average family size increased only moderately, from . to . people, because of the increase in mortality; the size of households including one of the two surviving grand-parents more than years of age rose from to . people. at the onset of the ndt, life expectancy at birth could have been about years for males and years for females, but rises to . years and . years, respectively, at the age of . by the end of the ndt, due to the transition to higher mortality values, life expectancy at birth is about years in both sexes, but years for males and . years for females at the age of ; % of the population is under years old and the median age is . these figures must be taken rather as orders of magnitude in order to try to indicate the trend during the ndt, rather than precise statistical data. what consequences should we expect from a very young population, with a birth rate and a median age identical to that of niger today ( per in : direction de la statistique )? one of the effects of an increase in the growth rate caused by a combination of high birth and mortality rates is that families, on average, have more surviving children but families do not last as long. in societies with low life expectancy at birth, extended families, first to collaterals, are taken as the standard relative to nuclear families, with "their patriarchal or matriarchal and nepotistic tendencies that stifle individual initiative" (kuznets : cited by mcnicoll . to individuals, mainly children, they provide a form of life (or survival) insurance when mortality causes families to fall apart. in many traditional village societies, the inhabitants make a distinction between the descendants of the original founders of the village and other inhabitants who do not have this ancestral link (mcnicoll ) . villages have historically expanded by fission in most peasant societies, with the establishment of "daughter villages" as population grows. the resulting pattern of clustered hamlets, each village typically having a few hundred homes at most, is largely found in asia and the middle-east. in the context of open borders, the inhabitants can create new villages in distant settlement areas. new world settlement evidence for a two-stage neolithic demographic transition early sedentism in the near east new perspectives in archaeology nunamiut demography history: a provocative case the naron: a busman tribe of the central kalahari modèles de la démographie historique busman birth spacing: a test for optimal interbirth intervals testing adaptiveness of culturally determined behavior. do bushman women maximize their reproductive success by spacing births widely and foraging seldom paleoanthropological traces of neolithic demographic transition testing the hypothesis of a worldwide neolithic demographic transition. corroboration from american cemeteries (with comments) estimates of upper palaeolithic meta-population size in europe from archaeological data demografia de la difusion neolitica en europe y los datos paleoantropologicos subsistence strategies and early human population history: an evolutionary ecological perspective the population problem: a study in human evolution the history of the human population the food crisis in prehistory determinants of lactational amenorrhea direction de la statistique et des comptes nationaux. . l'emploi, le chomage et les conditions d'activité dans la communauté urbaine de niamey the limitation of human population: a natural history advances in human reproductive ecology the ecological context of human ovarian function lactation, nutrition and fertility and the secretion of prolactin and gonadotrophins in mopan mayan women the signal of the neolithic demographic transition in the levant demographic archaeology resources, rivalry, and reproduction: the influence of basic resource characteristics on reproductive behavior demographic methods suckliong patterns and post-partum amenorrhoea in bangladesh western indians comparative environments, languages, and cultures of western american indian societies codebook for western indians data nursing frequency, gonadal function and birth spacing among !kung hunter-gatherers life in neolithic farming communities. social organization, identity and differentiation people and space in early agricultural villages: exploring daily lives, community size, and architecture in the late pre-pottery neolithic foraging, farming, and social complexity in the pre-pottery neolithic of the southern levant: a review and synthesis population growth and the beginning of sedentary life among the !kung bushmen the intensification of social life among the !kung bushmen the !kung san: men, women and work in a foraging society population dynamics of humans and other animals the resumption of ovulation and menstruation in a well-nourished population of women breastfeeding for an extended period of time the effect of improved nutrition on plasma prolactin concentrations and postpartum infertility in lactating gambian women reprinted for the royal economic society consequences of rapid population growth: an overview and assessment the neolithc revolution of bacterial genomes standard cross-cultural sample maternal nutritional status is inversely associated with lactational amenorrhea in sub-saharan africa: results from demographic and health surveys ii and iii demographic analysis. chicago: aldine-atherton malthus revisited: exploring medium-range interaction between economic and demographic forces in historic europe increase in natural fertility during the early stages of modernization: canadian indians case study sedentism and changing fertility patterns in northern athapascan isolate a note on the demographic concomitants of sedentism demographic patterns of sedentary and nomadic juang of orissa correlates of the long postpartum taboo: a cross-cultural study wildlife population growth rates child transport, family size and the increase in human population size during the neolithic twenty-four hour patterns of prolactin secretion during lactation and the relationship to suckling and the resumption of fertility in breast-feeding women lactational amenorrhoea in well-nourished toba women of formosa comparative study of breastfeeding structure and its relation to human reproductive ecology how can a homeostatic perspective enhance demographic transition theory? dynamics of human reproduction: biology, biometry, demography lactation and birth spacing in highland new guinea attenuation of nursing-related ovarian suppression and high fertility in well-nourished, intensively breast-feeding amele women of lowland papua new guinea acknowledgments my thanks to eric ledru, stephan naji, lyliane rosetta for different parts of this manuscript. the cause of the neolithic fertility transition put forward in this article, beyond the proxy variable represented by sedentism, is the impact of an unprecedented shift in the energetics of female mobile foragers over years in the levant. however, this unprecedented increase in fertility did not result in demographic saturation of the planet as might be expected but, probably only in a growth rate typical of preindustrial populations of about . - . %. the hypothesis is therefore that, with the appearance of village life and the corresponding increase in local population density, higher mortality soon followed the increase in fertility. this would have produced the net effect of an appreciable increase in the population during the ndt and, at the same time, a reduction in life expectancy at birth. the difficulty, however, lies in detecting the signal of the mortality transition in the (bio)archaeological data available. this is the first new challenge.a new question relates to the insights provided by the ndt scenario that help us to understand the archaeological data, and vice versa. at which point in the timing of the fertility transition did archaeological artefacts appear, or disappear, that are interpretable in terms of indicators of economic, social and ideological reorganisation or adjustment? what changes in the archaeological data can be linked to the tempo or the scenario of the ndt? (for a review see kuijt a, kuijt and goring-morris ) . the second challenge is the integration of the archaeological data (kuijt and goring-morris , belfer-cohen and bar-yosef , kuijt a , b into the model of the ndt and the reverse, in order to understand the multidimensional aspects of the first human experiment in unprecedented population concentrations and the birth of a new world. key: cord- -pqy bikp authors: hayes, adrian c.; jupp, james; tsuya, noriko o.; brandon, peter title: book reviews date: journal: j popul res (canberra) doi: . /bf sha: doc_id: cord_uid: pqy bikp nan the common picture of the health of populations around the world today is confusing. on the one hand, death rates in most developing countries have declined dramatically over the past years and people live longer; on the other hand, infectious diseases once thought to have been conquered are making a comeback and hiv/aids could become the worst epidemic in history. in this book mcmichael argues that the way to make sense of this paradox is to use a broad human ecological perspective on population health. he gives a masterful and engaging account of the 'long history of the changing patterns of human ecology and disease' from the pleistocene to the dawn of the twenty-first century. patterns of health and disease are examined as the product of ever-changing interactions between human biology and the social and physical environments. new patterns of disease emerging today may reflect the fact that humans are stressing ecological life support systems beyond the limits of their tolerance. in the space of this review i can only mention a few of the many topics mcmichael skilfully weaves into the story. biology establishes some fundamental parameters for population health. mcmichael's first three chapters discuss relevant aspects of human evolution. human and chimpanzee genuses diverged in africa - million years ago as the cooling of the pliocene produced an ecological niche 'for an ape able to survive mostly out of the forest' (p. ). then the enhanced cooling of the pleistocene (beginning about million years ago) led to rapid speciation of the homo genus. it is now generally agreed that a succession of homo species migrated out of africa, with extensive periods of co-existence among different homo species. homo sapiens and homo neanderthalis, for instance, shared much of western eurasia for thousands of years before the latter species became extinct around , years ago. since then homo sapiens has been the sole survivor of the homo genus -and, as mcmichael poignantly points out, if the current anthropogenic decline of species continues, it could become the sole representative of the whole great ape family. many distinctive characteristics of human biology were established as adaptations to environmental conditions of the pleistocene. as conditions changed, some of those adaptive responses became no longer so 'adaptive', and the resulting imbalances between biology and environment can manifest themselves as a tendency to disease. one example discussed by mcmichael is adaptations in insulin metabolism. insulin is an 'ancient vertebrate hormone' (p. ) that plays a vital role in the way the human body processes ingested carbohydrates and fats and converts them into energy for cell metabolism. the australopithecines (our pre-homo ancestors, including the celebrated 'lucy') appear to have been mostly vegetarian. as the tropical vegetation thinned during the global cooling of the pliocene, however, 'the survival benefit gained from supplementary high-quality meat protein would have increased ' (p. ) . certainly the hominines (species of the homo genus) emerging during 'the even cooler pleistocene … took to meat-scavenging and hunting … the product of an evolutionary branch that invested in cognition rather than mastication ' (pp. - ) . we would expect natural selection to have a corresponding effect on the way the body uses insulin. mcmichael, drawing on the work of j.v. neel and others, hypothesizes that 'meat-dependent hunter-gatherers may have reached the end of the pleistocene, around , years ago, with a reduced insulin sensitivity by comparison with their australopithecine ancestors ' (p. ) . this sets the stage for mcmichael to advance a 'provisional thesis' (p. ) to account for the prevalence pattern of 'type ii' (non-insulin-dependent) diabetes in the world today. the prevalence of type ii among major population groups varies by more than a factor of ten, and the variation is still striking even after controlling for obesity. europeans have low rates. assuming that reduced insulin sensitivity was the 'background' genotypic condition , years ago mcmichael speculates that a few neolithic populations might have diverged from this condition and developed a more insulin sensitive metabolism. moreover those few populations could well have included the proto-europeans, who were after all among the first to develop settled agriculture, implying a diet with more carbohydrates again. middle eastern farmers domesticated not only plants, but also goats, sheep, and later cattle. 'from around , - , years ago these agrarian communities began consuming milk and milk products. the result, today, is that genetically based tolerance of lactose (milk sugar) is much more prevalent in european than in most non-european populations' (p. ). genetic adaptation of populations to diets with differing glycaemic loads could help account (in conjunction with dietary changes and obesity levels) for their different levels of glucose intolerance and frank diabetes. mcmichael's line of reasoning takes more twists and turns than i can repeat here, and lack of direct confirmatory evidence means much of it remains speculative. as the late stephen jay gould ( : ) remarked, paleoanthropology has 'more minds at work than bones to study'. but his account shows how mismatches between biology and environment can affect population health. 'patterns of health and disease are the product of antecedent biological evolution interacting with current social and physicalenvironmental conditions' (p. ). other selection pressures he discusses, aside from food availability, are climate (leading to adaptations in skin pigmentation and the immune system) and infection (chapter includes a fascinating account of the co-evolution of parasite and host in the case of malaria). chapters - explore how a succession of changes in human ecology during the period of recorded history have affected patterns of health and disease by virtue of their impact on the co-evolutionary interplay between microbes and humans. this interplay is ubiquitous wherever there are human populations and is older than 'history' itself. when early humans became meat-eaters they exposed themselves to various animal parasites; when they migrated out of africa they encountered unfamiliar microbes. in these chapters, however, mcmichael emphasizes three broad historical transitions. the first corresponds to the rise of settled agriculture and the concentration of population in the early civilizations of the middle east, egypt, south asia, east asia and central and south america. this created a new web of relationships among animals, humans and microbes, facilitating the migration of microbes from animal to human populations. 'smallpox arose via a mutant pox virus from cattle. measles is thought to have come from the virus that causes dis-temper in dogs, leprosy from water buffalo, the common cold from horses, and so on' (p. ). most of the well-known infectious 'crowd' diseases appear to have developed during this transition; although the 'leap' from animal species to humans can still occur today, of course, as hiv and sars attest: writing before the recent sars outbreak mcmichael notes: 'in southern china, the intimate pig/duck farming culture creates a particularly efficient environment in which multiple strains of avian viruses infect pigs. the pigs act as "mixing vessels", yielding new recombinant-dna strains of virus which may then infect the pig-tending humans ' (pp. - ) . each of the ancient civilizations acquired its own repertoire of locally evolving infectious diseases. the second transition corresponds to the era of fluctuating contact among the eurasian civilizations through trade and warfare from around bc to ad . mcmichael builds on mcneill's ( ) thesis that this contact resulted in the transmission and swapping of microbes, leading to episodic epidemics followed by periods of gradual re-equilibration between the infectious agent and human host population. the complex aetiology of the black death in mid-fourteenth century europe, for example, seems to include an outbreak of bubonic plague in china during the s. 'after many turbulent centuries, this transcontinental pooling resulted in an uneasy eurasian equilibration of at least some of the major infectious diseases' (p. ). the third great historical transition refers to europe's exploration and conquest of distant lands, and (using language reminiscent of diamond ) the export of 'its lethal, empire-winning, germs to the americas and later to the south pacific, australia and africa' (p. ). the large aztec and inca populations had no herds of wild animals they could domesticate and remained relatively free of 'crowd' infectious diseases until they were decimated by smallpox, measles and influenza introduced by europeans. falciparum malaria and yellow fever were brought to the americas in the seventeenth century by the trans-atlantic slave-trade. in similar fashion the aborigines of australia suffered deadly epidemics following the arrival of europeans on that continent. and within years of captain cook's first visit to hawaii in the native population declined from around , to less than , . mcmichael points out that the third transition was more a 'dissemination' of microbes that had co-evolved with the eurasian population to other parts of the world than an 'exchange'; and he is sceptical that syphilis was really introduced to europeans from the amerindians, as is often claimed. in any event the third transition represents another major process re-equilibrating the balance between microbes and humans, this time across transoceanic populations. are we experiencing a fourth major historical transition today? around many experts thought that tuberculosis, cholera and malaria would soon be conquered; it was time 'to close the book on infectious diseases', declared the us surgeon-general (p. ). but now these diseases are increasing again, and a host of other diseases or their pathogens have been newly identified; they include lyme disease, hepatitis c and e, human herpes viruses and , ebola virus and legionnaires' disease. something 'unusual' seems to be happening to patterns of infectious diseases (p. ). to explain this mcmichael suggests we must look at contemporary human-induced social-environmental changes which provide new opportunities for microbes to invade and colonize the human body: worldwide urbanization, intravenous drug use, changing sexual practices, changes in medical practice (blood transfusion, organ transplants), intensive food production, poverty and inequality, irrigation, deforestation, eutrophication of rivers, and so on. in the last three chapters mcmichael draws together these themes in a more prospective view, detailing the risks to population health inherent in the way we are currently 'depleting or disrupting many of the ecological and geophysical systems that provide lifesupport' (p. ). chapter includes a discussion of the health impact of climate change. as in his earlier work ( ) mcmichael adds his voice, with eloquence and authority, to the imperative of establishing more sustainable ways of living. mcmichael's book is impressive in the way it marshals research findings from diverse fields, and even more important for the way it clarifies our contemporary situation. however, in telling the story about population health from a social ecological perspective his narrative is ahead of his analytics. he criticizes the conventional epidemiological approach (taking the individual as the unit of analysis) for its reductionism, but gives no systematic exposition of his own more holistic conceptual framework detailing precisely how it is 'some important health-determining factors operate essentially at the population level' (p. ). similarly his conceptualization of anthropogenic environmental change (building on peter vitousek and others) is pretty all-embracing and not yet structured to help us focus on those parts or processes most relevant for population health. the persuasive force of this book comes more from the weight of its examples of social-ecological processes influencing patterns of health and disease in populations than from any systematic theory describing these relationships. mcmichael is clearly aware of these limitations; we hope he can address them in future work. a more explicit analytics will facilitate a more felicitous telling of the story. experts and advanced students from any number of population-and healthrelated disciplines will find this book useful and stimulating. demographers will especially like the way it clearly positions 'population' centre stage; and the book's central thesis is certainly a boost to those of us who like to see demography in a strategic position at the intersection of the human and natural sciences. for those working in family planning, there is a challenging section on the health consequences of modern reproductive interventions ( pp. - ). institutions which have supported this fine work deserve some credit too. mcmichael was professor of epidemiology at the london school of hygiene and tropical medicine when he wrote this book; he is now with the national centre for epidemiology and population health (nceph) at the australian national university. the disciplinary structure of modern universities is not always conducive to bold synthetic research like mcmichael's. this book shows how important it can be: in fact the future health of human populations could well depend on it. the basic proposition of this interesting and timely book is that 'irregular migration occurs because states make rules about who can legally cross their borders. under conditions of globalization, these rules promote transnational economic activity, but limit who can work and stay ' (p. ) . in other words, there is a contradiction between increasing globalization and a declining willingness to accept mobility of labour as opposed to capital and goods. this contradiction is especially apparent in the european union and the united kingdom, with which much of this book is concerned. britain, france and the netherlands had a long tradition of free entry for imperial subjects, which they eventually found politically embarrassing. they now have the practice of free entry for european union subjects, which they may also find embarrassing as the eu extends to eastern europe and even turkey. with its focus on britain, this study sees irregulars as mainly those who arrive through legal means but then work, which they are forbidden to do. peoplesmuggling, which has become so controversial, is not central to their analysis. because the majority entering britain do not need visas, it is easy to get in. because there is no national identity card, it is easier to work illegally than in most european states. serious criminal activity is a matter for the police, who are relatively indifferent to breaches of immigration rules. the basic problem remains that britain, like several other european states, does not really have an immigration program. those who wish to remain permanently and to become citizens must either be closely related to those already there, or make a successful asylum application, or gain access to the very restricted working-visa or business-visa system. only recently, and since the publication of this study, has the government moved towards developing a coherent system allowing a quota of permanent residents; it has done so in response to widespread hysteria, worked up by the populist media, against asylum seekers. one weakness of this study is that it concentrates on economic motivations; yet the recent surge of asylum seekers, as in australia, includes many who are genuinely fleeing wars in afghanistan and iraq. the british situation is made more acute by many from collapsing african states, or balkan romanies, making well-based claims of ethnic persecution. these latter will probably have full access to britain once their states have joined the european union. at the core of this study is an analysis in depth of irregular migrants living and working in london. the groups chosen are brazilians, who have no strong historic connections with england; poles, who have stronger links; and kurdish turks, the only ones who can make plausible claims to be asylum seekers. other than some of the kurds -who are highly politicized -the irregulars simply come to make more money than at home, have no real desire to settle permanently and are ready to work for low wages and below their level of qualification. one interesting feature of these irregulars, which may well apply generally, is that they are young and well educated. they may come from poor countries but they are not peasants or labourers. what little we know about asylum seekers suggests that they are also well educated and skilled. the difference is that they have few places left to go, whereas many of the openly 'economic irregulars' have every intention of returning home in due course. because they are relatively well-qualified, many of those studied here have access to the variety of non-government organizations which have sprung up to help them and represent them to the authorities. they are certainly not voiceless even if inclined to avoid direct contact with government for fear of deportation. because london has a long history of immigrant labour in service industries, there does not seem to be much concern with the present situation. as host to millions of tourists it needs a mobile labour force, and it does not have a serious unemployment problem except in some declining enclaves in the east end. many of those interviewed have worked illegally for years and have rarely encountered any attempt to discourage or remove them. there is a contrast between this liberal approach to casual labour and the much stricter attempts to discourage permanent settlement. however, the flood of asylum seekers in recent years is changing this. the book's publication was too early to account for the recent moves in britain towards a regime reminiscent of that in place in australia. as presented here the british authorities do not really mind people coming to work in low-wage industries because they do not expect them to settle. london is now so cosmopolitan that racial tensions are less politically significant than in some smaller cities which have recently experienced violent reactions. as is regrettably common in texts published in europe and north america, there are only passing references to australia. this reflects our isolation, which also makes the 'dilemmas' of irregular migration less pressing than for states with long land boundaries or short sea crossings. however, australia does have a complex, planned and longstanding immigration program, with some principles and practices extending back for over a century. this is in contrast to the united kingdom situation studied at the heart of the book. some issues which are of interest to australian scholars and addressed by this book include: will irregular immigration increase despite increasingly rigorous attempts to prevent it? does the admission of large numbers of students, tourists and working-holiday temporary migrants make this more likely to happen? is flexibility needed in assessing asylum seekers as against 'economic migrants'? how can immigration policy be insulated against populist agitations and political expedience? can sydney hope to be a 'world city' without a degree of 'irregular migration' to supply transient labour in services? does our expanding relationship with the island states of the south pacific make regularization of immigration on a more generous basis more likely? does it really matter if there are thousands of 'irregular migrants' working in the economy? how can people-smuggling, trafficking in women, drug-smuggling and terrorism best be controlled without draconian restrictions on legitimate movement? this is an interesting and useful book. its tendency to see all movement as essentially motivated by economic inequality is of prime importance, even if that is only part of the story. globalization without liberal migration regimes, on this view, could be oppressive. but are the rich societies ready to modify this? this study ends on the note that 'globalisation has consisted in the development of the world economy under conditions most favourable for capital and the first world countries, and under terms that discriminated against the developing countries in the liberalisation of trade. … for these reasons, it is doubtful whether an international regime for managing migration, would be a step towards international justice' (p. ). australian national university this volume offers anthropological accounts of the evolution, production, and consumption of various social policies in contemporary japan. consisting of nine chapters, it is a collection of papers prepared originally for an international conference. chapter , by goodman, discusses the evolution of applied anthropology, and explains what anthropology can offer to the studies of social policy. the anthropology of social policy is not only the study of meanings ascribed to slogans and symbols associated with the policy but also that of its production and consumption. as goodman argues, social policies not only emerge from a particular socio-cultural context, but they also provide important clues to how social values are constructed and altered. chapter , by bestor, attempts to sketch a 'cultural biography' of civil society in contemporary japan. it first traces the postwar development of the notion of civil society; it next examines the multiple uses of related terms such as civil society, volunteerism, npo, and ngo; and then provides an example of the development of civil society by describing a sudden rise in volunteer activities and the enactment of the npo law following the hanshin earthquake in . instead of devoting many pages to explanations of the meanings of different terms, the chapter would have been more interesting if it were focused more on the processes that gave rise to volunteerism and the ensuing legislation by illustrating the interaction between volunteer activities and the policy responses. in chapter , roberts analyses the problems associated with low fertility, by examining programs within the angel plan -the comprehensive policy to increase the rapidly falling birthrate -and public discourse associated with its implementation. roberts demonstrates that the policy initiatives are not consistent with, therefore not effective in altering, the prevailing gender division of labour. by identifying some of the voices influencing the production and implementation of the policy, she also illustrates the nature of changing social norms and the roles of policy in bringing about such changes. although some demographic facts are misrepresented, the chapter nevertheless offers vivid information regarding how the plan is produced and consumed, therefore furthering our understanding of the importance and difficulties of balancing work and family in contemporary japanese society. in chapter , stevens and lee analyse how two sets of government policies, those of the ministry of health and welfare and the others of the ministry of justice, influence the provision of maternal and child healthcare for foreigners in japan. they argue that legal and cultural stresses, exerted by the way the policies determine the eligibility and provisional guidance for healthcare, make it difficult for foreign women to have the care they need, and that in turn leads to higher-risk pregnancies. public policies and laws are influenced by the perception of ethnicity, and the lack of policies to deal specifically with health problems of foreign mothers suggests a dual reality of health and welfare in different segments of the population. however, their arguments are not fully supported by empirical evidence, according to which the mothers who suffer higher health risks are those from developing countries in southeast asia whereas the risks for other foreign mothers are similar to, or significantly lower than, those for japanese mothers. providing that foreigners comprise vastly different groups, it seems necessary to account for their differences in socio-economic status, demographic features, and legal status before we determine whether foreign mothers indeed suffer higher health risks. chapter , by ben-ari, examines the interrelation between the organizational features of japanese preschools and the way by which they are predicated on notions of normal development of children. based on participant observations, visits to childcare institutions, and secondary analyses of administrative documents used by these institutions, ben-ari shows how organizational arrangements of institutions of early childhood education are related to the ways that children are socialized according to a uniform set of ideas that the state deems normal and ideal. this chapter is, like chapter , an example of practical anthropology at its best. it offers useful and interesting information based on two primary methods of applied anthropology: field work and content analysis of documents. in chapter , goodman analyses the 'discovery' of child abuse in japan and the development of social policy to deal with the problem. his view is that the upsurge of reported cases of child abuse in the s was largely a result of the campaigns by the media and child-welfare institutions. mothers are found to be the main abusers of children, and these groups viewed the increasing child abuse as a consequence of nuclearization of the family, combined with the prevalent myth of motherhood. goodman shows that through the implementations of regulations and policies, this discovery altered the relationship between the state and parents by giving greater powers to authorities to intervene in what had previously been seen as the exclusive and private domain of the family. chapter , by thang, offers an overview of programs to promote interaction between the elderly and school-aged children and teenagers in japan. through an attempt to interpret intergenerational interactions in the context of the japanesestyle welfare society, thang seeks to show the needs for and significance of intergenerational interaction programs. although we cannot deny the need for programs to promote intergenerational interactions, i cannot help feeling that such programs are supplementary in an array of policies designed to support and care for the elderly. given the rapidity of population ageing and the pervasiveness of its socio-economic, demographic, and political consequences, more attention should be paid to how these programs are related to mainstream elderly policies such as the golden plan and the long-term care insurance, and to how these policies and programs together alter the perceptions and treatment of the elderly in contemporary japan. in chapter , tsuji examines the evolution of death-related policies in japan over the last years. tsuji shows that mortuary practice is shaped by interplay among policies, individual actors, and traditions, being conditioned by wider socio-economic and demographic changes. though it is a little too long on explanations of prewar development, i found the chapter interesting and informative, illustrating skilfully that since meiji the government has used death policies to exert control over the family and individuals, and that mortuary practices have changed in recent decades in the face of constraints driven by low fertility. chapter , by mackie, discusses some of the ways in which social policy affects individuals differently. it argues that the archetypal citizen in the contemporary japanese political system is a male, heterosexual, able-bodied, fertile, white-collar worker. this in turn suggests that our understanding of citizenship can be broadened if we view citizens as embodied individuals whose positions are situated somewhere in a spectrum, shaped and constrained by legal and institutional structures. while the typology of citizens provided by this chapter is useful in understanding how citizenship is defined by the society, it falls short of explaining how changes in social policy are related to changes in the notion of citizenship in contemporary japan. there are general weaknesses in the volume, stemming largely from the very nature of the enterprise. in all, however, the volume provides useful insights into how problems and policy issues shared by many industrialized countries are tackled in japan. thus it will be of interest not only to japan specialists but also to those who are interested in social policy in industrialized societies in general. is an ambitious book. the first book in a series on the australian economy and society, it provides informative analyses about education, work, and welfare in australia over the last decades of the twentieth century. this important work on contemporary australia creatively presents data on shared and divergent attitudes among australians, social trends over time, comparisons among social groups, and comparisons with other nations. the book is distinctive in using large, representative samples of australians and persons from other nations to make conclusions and inferences. three principal sources of data are used: the international social science surveys/australia, the international social survey program, and the international survey of economic attitudes. combined, the three surveys yield a sample numbering over , individuals. the surveys are nationally representative and, depending upon the topic under investigation, permit the authors to make generalizations to the populations as a whole. with the improvements in measurement theory and survey questionnaire design, the authors can provide authoritative statements about people's attitudes and behaviours within countries and compare australians' attitudes and behaviours to those of persons in other nations. with some exceptions, the nations with which australia is most often compared are english-speaking or european. two chapters that provide interesting applications of the comparative analysis approach using survey data are chapter , 'conflict between the unemployed and workers in nations' and chapter , 'participation in the labour force'. the tabulations in each chapter develop the authors' stories as eloquently as the accompanying narratives. furthermore, the large amounts of data collected from the surveys permit the authors to exploit more advanced multivariate techniques. throughout the book, various multivariate modelling strategies are used to better understand relationships between such topics as education and earnings; job complexity and earnings; upbringing and attitudes about trade unions; and risky lifestyles and ideals about societal responsibility for diseases. obviously, in the interests of science and effective policy development, debate should surround the methods used and the conclusions reached. notwithstanding the need for such debate, the book carefully documents its methods and justifies the statistical approaches taken. readers concerned about empirical social science will welcome the multivariate models featured in the book, especially since most of its predecessors, which aimed for the same grand scale and scope, often omitted multivariate models. that omission was rarely made by choice, but was usually due to data constraints. attention to methods, creative use of surveys, and strategically placing findings in national and international contexts produce some fascinating findings in the book. some of the more notable findings include workers' desires for job security, even if it means less pay; stronger support for trade unionism among public service employees than among blue-collar workers; australians' desires to see the influence of unions no further weakened after many years of sustained government efforts to do so; a tension between australians' feeling sorry for their fellow australians who have suffered from diseases as outcomes of risky health behaviours on the one hand, yet also feeling one must take responsibility for one's own life-style choices on the other hand. and, lastly, a finding that australians do more complex jobs than their counterparts in five european nations, but that complexity is not the most important determinant of salaries. rather, the apparent determinants of australian salaries are status and maleness. the book accomplishes its goal of clearly and concisely presenting its findings and interpreting what they mean for contemporary australian life. topic vi, 'retirement', which contains three chapters, is a good example of the clarity and compactness of the writing style and presentation of facts. however, readers may sometimes find the book too dense and the huge number of graphs, figures, statistics, replicated survey questions, and technical notes distracting instead of illuminating. perhaps the commendable effort to document rigorous scientific analyses is occasionally counterproductive. overall, the work is essential reading and it offers researchers, policymakers, and others concerned about australia's future a myriad of social and economic data in one source. if this book is indicative of future volumes in the series, then the series will have great utility. guns, germs and steel: the fates of human societies planetary overload: global environmental change and the health of the human species plagues and people key: cord- - z ykb authors: healing, tim title: surveillance and control of communicable disease in conflicts and disasters date: journal: conflict and catastrophe medicine doi: . / - - - - _ sha: doc_id: cord_uid: z ykb nan tim healing • to describe the principles of health surveillance in conflict and disaster situations • to assist in organizing a health surveillance system in conflict and disaster situations • to describe the principles of control of communicable diseases in conflict and disaster situations • to assist in organizing a response to outbreaks and epidemics • to introduce the challenges associated with health surveillance and communicable diseases in conflict and disaster situations there are five fundamental principles for the control of communicable disease in emergencies: • rapid assessment -identify and quantify the main disease threats to the population and determine the population's health status • prevention -provision of basic health care, shelter, food, water, and sanitation • surveillance -monitor disease trends and detect outbreaks • outbreak control -control outbreaks of disease. involves proper preparedness and rapid response (confirmation, investigation, implementation of controls) • disease management -prompt diagnosis and effective treatment rapid assessment has been dealt with elsewhere in this book as have the prevention aspects of disease control (adequate shelter, clean water, sanitation, and food, together with basic individual health care). this chapter therefore covers surveillance, outbreak/epidemic control, and public health aspects of disease management. the topics are dealt with in general terms. more details can be found in references. disasters, particularly conflicts, by damaging or destroying the infrastructures of societies (health, sanitation, food supply) and by causing displacement of populations, generally lead to increased rates of disease. outbreaks and epidemics are not inevitable in these situations and are relatively rare after rapid-onset natural disasters, but there is a severe increase in the risk of epidemics during and after complex emergencies involving conflict, large-scale population displacement with many persons in camps and food shortages. in most wars more people die from illness than from trauma. preventing such problems, or at least limiting their effects, falls on those responsible for the health care of the population affected by the emergency. they must be able to • assess the health status of the population affected and identify the main health priorities • monitor the development and determine the severity of any health emergency that develops (including monitoring the incidence of and case fatality rates from diseases, receiving early warning of epidemics and monitoring responses) at first sight, undertaking public health activities in emergencies, especially in conflicts, may seem to be difficult or impossible. the destructive nature of warfare may prevent or inhibit the provision of adequate food and shelter, of clean water and sanitation and vaccination programs. despite the difficulties that warfare imposes, it is generally possible to undertake at least limited public health programs, including disease surveillance and control activities. in other types of disaster public health activities may be expected to be less affected by the security situation than in a war (although aid workers may be at risk if populations are severely deprived of resources such as food, shelter, water, or cash), and with limited access and damage to communication systems and other parts of the infrastructure assessment, surveillance and control activities can be severely restricted. for example, following the pakistan earthquake late in access was severely restricted for some time and the urgent need to treat the injured and provide food and shelter meant that the limited transport available was heavily committed. the surveillance and control of communicable disease require data which can be collected in one of three ways: . surveillance systems -covering all or at least a significant proportion of the population . surveys -in which data are collected from a small sample of the affected population considered to be representative of the whole . outbreak investigations -in-depth investigations designed to identify the cause of deaths or diseases and identify control measures although the latter two can provide valuable information for disease control and form part of the surveillance process, proper control of disease requires regular monitoring of the overall disease situation, which in turn requires the establishment of a properly designed health surveillance system. it is important therefore that responsibility for surveillance activities is defined at the beginning of planning for an aid mission. generally speaking, a team will be required, including a team leader (often an aid agency health coordinator), who should ideally have surveillance experience, clinical workers, a water and sanitation specialist, and representatives of the local health services and communities. the team may also need clerical, logistic, information technology and communications specialists. the world health organization defines health surveillance as "the ongoing systematic collection, analysis and interpretation of data in order to plan, implement and evaluate public health interventions." data for surveillance must be accurate, timely, relevant, representative, and easily analyzed, and the results must be disseminated in a timely manner to all who need to receive them. in addition the data collected, the methods used for collection and the output must be acceptable to those surveyed (health-care professionals and the population). in emergencies the time that can be given to surveillance by medical personnel is likely to be limited and surveillance activities will be far from the minds of most of those involved. therefore the methods used need to be rapid, practical, and consistent, and while the greatest possible accuracy must be achieved, "the best must not be the enemy of the good." it is necessary to strike a balance between collecting large amounts of information ("what we would like to know") and collecting too little which can lead to an ineffective response. those responsible for establishing surveillance programs must therefore try to determine what is really needed ("what we need to know"). it is better to err on the side of too much than of too little. ideally any existing surveillance system should be used. there is no point in establishing a system if one already exists, unless the existing one is inadequate or inappropriate or has broken down irretrievably. surveillance systems for use in conflict and disaster situations should therefore adhere as far as possible to the criteria given in table . . notes on these criteria: complexity and inflexibility are incompatible with surveillance systems generally and particularly when operating in emergencies where collection of data may be difficult and where situations can change very fast. defining what you "need to know" will allow you to set up the appropriate data collection methods (questionnaires, sites, etc.) and to design the system so that it can obtain and handle the information required. information that is accurate but out of date is useless for immediate disease control purposes and of little value for forward planning. communications therefore form an integral part of any surveillance system. do not try to overreach when setting up a system. for example, expatriate staff may best be used to recruit local staff for the system and in supervisory activities rather than in collecting data. this criterion is certainly a goal to aim for as sustainability must be the target for all aid work. however, there may be situations where an emergency system is needed rapidly and where it cannot readily be integrated into existing systems or be developed as a new long-term system. . based on standardized sampling methods the sampling system must use the same data collection methods throughout if data are to be comparable. ideally this should be methods that are internationally agreed and approved. agreement should be sought for the methods from the other agencies on the ground to ensure consistency. without case definitions that are agreed by all parties the likelihood of success of a surveillance system is very low. this is especially so when laboratory support is minimal or absent since clinical case definitions have to be drawn very tightly if different diseases are not to be confused. routine surveillance requires more than material from ad hoc sources. sites such as medical centers (in towns, villages, or refugee camps), hospitals, and/or public health units should be recruited. the more comprehensive the coverage of the system, the more likely is it that the data will be accurate and complete and that problems will not be missed. such coverage can be problematic. the coverage of the different systems that can be used is discussed below. the data collected and the methods used should ideally fit in with systems that are operating or have previously operated in the area. following from criterion , if systems are already in existence or in abeyance but revivable then this should be done so as to ensure compliance by local health-care services and continuity of data collection and analysis. existing records are of considerable value for predictive purposes. knowledge of past problems makes it possible to anticipate future trends and problems and allows for early planning decisions. if several health agencies are operating it is essential to ensure collaboration among them in surveillance activities to avoid confusion and duplication of effort. . involve collaboration with local services so as to avoid duplication as above, early involvement of local health and surveillance services will reduce workloads and avoid duplication of effort. if those from whom the data are collected, those who are collecting the data, and those who will receive the results are unhappy with the system, the system is unlikely to operate effectively. these criteria can be used to evaluate a plan for a surveillance system and also, with some additions, to evaluate an existing system. however, failure to fulfil all these criteria need not rule out a system. in many emergencies it can be difficult to meet such a wide range of "best case" criteria, and the question that must be asked is whether the proposed system is capable of fulfilling its purposecan it provide sufficiently accurate essential information to those who need it when they need it? the emphasis of an emergency surveillance program may need to be altered as the situation changes especially if a particular item emerges as being of key importance. those running the surveillance program should use the data gathered and a continuous assessment of the general running of the system, to alter the program as required (preferably after consultation with relevant stakeholders). when designing health surveillance systems, it is essential to do the following: the population under surveillance may be relatively small and well defined (such as the population of a refugee camp) or a much less defined group such as mobile groups of refugees or idps or the population of a village, town, or region, the size of whose population may be unknown or may be fluctuating because of a disaster. establishment of denominators may therefore be difficult. even refugees or idp camps may present a challenge as, while the size of the population may appear to be (or actually be) stable, its makeup may vary over time because of movements in and out. if the age or sex makeup of the camp alters, the pattern of disease may also alter. both the number of cases detected and the rate of factors such as morbidity or mortality per unit of population are important values needed to inform emergency programs. those responsible for all aspects of health care need to know what numbers of cases are involved so as to ensure adequate provision of services (amounts of medicines, numbers of hospital beds, etc.). however, simple numbers are of little value in assessing trends and patterns since increases or decreases in numbers of cases (or numbers of deaths) may reflect changes in population size (resulting, for example, from population displacement) rather than a trend due to (for example) a particular disease. in addition, several rates (such as the crude mortality rate) are key indicators in defining health emergencies (see below). knowing the demography of the affected population is therefore important and all agencies working in an emergency should agree on and use the same population figures. the essential demographic data needed include the following: • total population size • population structure -overall sex ratio and the sex ratio in defined age groups -population under years old, with age breakdown ( - years) -this group has special needs and is usually a key factor in planning the emergency response -age pyramid -ethnic composition and place of origin -number of vulnerable persons (e.g., pregnant and lactating women, members of female-headed households, unaccompanied children, destitute elderly, disabled and wounded persons) at the outset it is therefore important to establish methods to obtain demographic data. often the best that can be managed initially is a rough estimate, but this can usually be refined later. it is helpful to use several methods and cross-check the figures to obtain the best estimate. surrogates of the whole population (such as those attending a clinic) may be the best that can be achieved early on. the ease with which such data can be obtained usually depends on the size and scale of the population under consideration. the demography of a well-run refugee camp is quite easy to obtain but that of a larger area may be much more difficult. a lack of knowledge of the size of a displaced group can be confounded by a lack of knowledge of the size of the resident population. in many countries with poor infrastructures, accurate census data are not available. in some instances tax records may be helpful if these can be obtained. it should be noted that demographic data, especially if they involve refugees and idps, can be politically sensitive and interested parties may place undue weight on any figures that are given. ideally, communicable disease surveillance should be nationwide (or at least "affected area wide"), drawing information from a range of health-care centers that cover a sufficient proportion of the population to ensure that the great majority of cases (preferably all) of the relevant conditions are reported. a surveillance system in a refugee or idp camp is effectively a miniature comprehensive system as it is possible to cover the whole population. there are situations where comprehensive surveillance is not possible and these often arise in disasters. damaged access and communications and staff shortages frequently mean that only limited numbers of reporting sites (sentinel sites) can be used. as far as possible these should be chosen to ensure a wide coverage of the area and also to maximize the proportion of the population that is covered. sentinel surveillance systems are inherently less satisfactory than comprehensive systems largely because they provide a much less complete coverage. the calculation of rates can sometimes be difficult or impossible; such systems can be very labour intensive, and important events may be missed. both types of system may rely on notification of cases based solely on clinical evidence (and this is the most likely situation in conflicts and disasters at least in the early stages), or may include laboratory verification of some or (preferably) all diagnoses. if there is more than one center involved in establishing the diagnosis (for example, a clinical department, a hospital laboratory, and a reference laboratory) the channels of reporting must be very carefully set up so as to avoid duplicate reporting. surveillance must provide information on key health indicators, which should include the following: the selection of information sought in these categories must be done carefully. it is neither possible nor desirable to monitor everything, especially in the early stages of a disaster response. at that stage (the acute phase) the priority of surveillance is the detection of factors that can have the greatest and most rapid effect on the population. in terms of communicable disease this means diseases that affect large numbers of people and have epidemic potential. in most instances this also means diseases for which effective rapid control measures exist. while gathering data on other largescale disease problems should not be excluded, the main surveillance and control efforts should be aimed where they can do the most immediate good. in the very early stages, only clinical information may be available since laboratory diagnostic services will probably be damaged or simply unavailable. however, this need not be a problem if the medical response is also geared to a syndromic approach. as the situation stabilizes, laboratory support becomes available, and longer term control measures can be supported, the surveillance can become more refined and additional diseases (for example, those which can cause severe morbidity and mortality in the longer term -such as tuberculosis, hiv or aids, and stds) can be added to the list. the main morbidity figures that are routinely sought are as follows: • incidence -the number of new cases of a particular disease reported over a defined period • attack rate (used in outbreaks -usually expressed as percentage) (also called incidence proportion or cumulative incidence) -number of new cases within a specified time period/size of the population initially at risk (× ). (e.g., if per , persons develop a condition over weeks, the ar/ip/ci is / , [ . %]) • incidence rate -number of new cases per unit of person-time at risk. in the above example, the ir is / , person-weeks. (this statistic is useful where the amount of observation time differs between people, or when the population at risk varies with time) • prevalence -the total number of cases of a particular disease recorded in a population at a given time (also called "point prevalence") (nb: prevalence "rate" is the number of cases of a disease at a particular time/population at risk) there are a number of ways of estimating morbidity. health information systems based on health center attendance are the most common but are passive and rely on who presents to the services. other ways of gathering morbidity data include the following: • surveys -in which data are collected from a small sample of the emergencyaffected population deemed to be representative of the whole (or from a particular group for a specific purpose) • outbreak investigations -which entail in-depth investigations designed to identify the cause of deaths or diseases and identify control measures as with disease, changes in numbers of deaths may reflect changes in population size. determination of rates is needed because mortality rate is an important surveillance indicator in an emergency. often the first indication that a problem is developing is an increase in death rate, especially in particular vulnerable groups. all deaths occurring in the community must therefore be recorded. the following indicators can provide the essential information to define the health situation in a population: • crude mortality rate (cmr) is the most important indicator as it indicates the severity of the problem, and changes in cmr show how a medical emergency is developing. cmr is usually expressed as number of deaths per , persons per day. if the cmr rises above / , per day (> / , per day for young children) an acute emergency is developing and the emergency phase lasts until the daily cmr falls to / , per day or below. • age-specific mortality rate (number of deaths in individuals of a specific age due to a specific cause/defined number of individuals of that age/day). in children this is usually given as the number of deaths in children younger and older than years/ , children of each age/day). nb: if population data for the under s are not available, an estimate of % of the total population may be used. • maternal mortality rate. maternal mortality is a sensitive indicator of the effectiveness of health-care systems. a maternal death is usually defined as the death of a woman while pregnant or within days of the termination of the pregnancy (for whatever cause) from any cause related to or aggravated by the pregnancy or its management. the -day cut-off is recommended by who but some authorities use a time of up to a year. maternal mortality rate = (number of deaths from puerperal causes in a specified area in a year/number of live births in the area during the same year) × , (or × , ) • cause-specific death rates (case fatality rates -usually given as a percentage). proportion of cases of a specified condition which are fatal within a specified time. case fatality rate = (no. of deaths from given disease in a given period/no. of diagnosed cases of that disease in the same period) × the following indicators must be measured: • prevalence of global acute malnutrition (includes moderate and severe malnutrition) in children - months of age (or - cm in height) (percentage of children with weight for height under two standard deviations below the median value in a reference population and/or edema) • prevalence of severe acute malnutrition in children - months of age (or - cm in height) (percentage of children with weight for height under three standard deviations below the median value in a reference population and/or edema) • • estimate number of children needing to be cared for in selective feeding programs • estimate number of additional calories per day provided by selective feeding programs immunization programs are a vital part of the public health measures undertaken following disasters. for example, measles vaccination is one of the most important health activities in such situations. the need for campaigns may be assessed on the basis of national vaccination records if they exist. in the absence of such records questioning of mothers may provide the information required, or children or their parents may have written vaccination histories with them (rare). the effectiveness of the programs undertaken can be assessed in defined populations by recording the percentage of children vaccinated. in less well defined populations an assessment of coverage may be made using the numbers of children attending clinics as a surrogate for the population as a whole. items such as water, sanitation, food, and shelter are essential to maintain a healthy population and prevent communicable diseases. depending on the circumstances it may be necessary to monitor these elements in the affected population. indicators such as number of consultations per day, number of vaccinations, number of admissions to hospitals, number of children in feeding programs are typically reported. other factors such as effectiveness of the supply chain, maintenance of the cold chain, and laboratory activities may also be surveyed. activities in related sectors such as water and sanitation, shelter and security may also be included. the major sources of health data will be hospitals and clinics (both national and those established by aid agencies), individual medical practitioners, and other health-care workers. specialized agencies should be able to provide data on particular needs (e.g., food, water, sanitation, and shelter). case definitions are an essential part of surveillance. if the diseases (or syndromes) that are to be covered by the system are not clearly defined, and if the definitions are not adhered to, the results become meaningless -changes from week to week are as likely to be due to changes of definition as to real changes in numbers of cases. this is especially important when laboratory confirmation is not possible. it is therefore important that all agencies working in an emergency agree to and use the same case definitions so that there is consistency in reporting. case definitions must be prepared for each health event or disease or syndrome. if available, the case definitions used by the host country's moh should be used to ensure continuity of data. several different sets of case definitions already exist, either in generalized form (for example, those produced by the centers for disease control in atlanta) or sets prepared for specific emergencies (e.g., the who communicable disease toolkit for the iraq crisis in ). standard case definitions may have to be adapted according to the local situation. it should be noted that such case definitions are designed for the purposes of surveillance, not for use in the management of patients, nor are they an indication of intention to treat the patients. when case definitions based purely on clinical observations are used, each case can only be reported as suspected, not confirmed (see table . ). although lacking precision, such definitions can make it possible to establish the occurrence of an outbreak. samples can subsequently be sent to a referral laboratory for confirmation. once samples have been examined and the causative organism has been identified, a more specific case definition can be developed to detect further cases. visits to surveillance sites and discussions with staff involved will help define the recording and data transmission systems required. the great advances in information technology that have been made in recent years have greatly facilitated the collection, recording, transmission, and analysis of surveillance data, but care must be taken that the systems put in place are appropriate. in areas where electricity supplies are problematical and communications poor it may be better to use a paper recording system and verbal data transmission by radio than a computerized system. data verification is essential for the credibility of a surveillance system. those responsible for surveillance systems must ensure good adherence to case definitions if a symptom-based system is in operation and that laboratory quality control systems operate where appropriate. regular assessments of record keeping and the accuracy of data transfer are required. triangulation of results from several sources can sometimes help to detect anomalies. frequency of reporting will usually depend on the severity of the health situation. in general, daily reporting during the acute phase of an emergency will be needed, although in an acute medical emergency (such as a severe cholera outbreak) even more frequent reporting may be necessary, especially if the situation is fluctuating rapidly. the frequency may reduce to (say) weekly as the situation resolves. who is to analyze the data and how it is to be analyzed must be established at the outset. in a relatively defined area such as a camp, a data analysis session may be the last of the daily activities of the person responsible for surveillance. if record keeping and analysis protocols have been carefully worked out initially this task is not necessarily a large additional burden. surveillance systems that cover larger areas and bigger and more diffuse populations usually rely on a central data collection point where designated staff analyze the data. use of such a system requires good data transmission systems. output is as important as input. collecting data without dissemination of results is a sterile exercise and tends rapidly to demotivate those who are collecting the data. there are some important points to consider: • the results of surveillance must be presented in a readily comprehensible form. • surveillance reports should be produced regularly and widely distributed to aid agencies, and to national and international governments and organizations. this will help those involved to understand the overall picture, rather than just that in the area where they are working, and will allow them to take informed decisions about future actions. surveillance systems should be evaluated constantly to ensure that they are working properly, that the data are representative, analysis is appropriate and accurate, and that results are being disseminated to where they are needed. the public health aspects of communicable disease control can be broadly divided into preventive activities (such as vector control and vaccination programs) and the investigation and control of outbreaks and epidemics. experience from many emergencies and disasters has made it possible to identify a number of syndromes or diseases that are most likely to occur in such situations (table . ). this makes it possible to plan activities and interventions on the basis of likely occurrences, even before those involved are present at the scene of the disaster, and to make initial purchases and establish stockpiles of appropriate medicines and equipment. "prevention is better than cure" and proper attention to preventive measures from the earliest stage of the response to the disaster will greatly reduce the risks to the health of the population from infectious disease. a key method of preventing communicable disease is the provision of shelter, adequate amounts of clean water, sufficient safe food, and proper sanitation (latrines and facilities for personal hygiene, clothes washing, and drying). arthropod vectors (mosquitoes, ticks) can be controlled by appropriate spraying programs and also by habitat management (e.g., the removal of places where water can accumulate and mosquitoes breed). provision of bed nets, particularly nets impregnated with insecticide, is effective for reducing infection with agents such as malaria and leishmania. control of rodents, by proper control of rubbish, by rodent proofing food stores, by attention to domestic hygiene and by use of rodenticides, will reduce the risks of transmission of rodent-borne diseases such as plague and lassa fever. medical waste includes laboratory samples, needles and syringes, body tissues, and materials stained with body fluids. this requires careful handling, especially the sharps, as infectious agents such as those causing hepatitis b and c, hiv and aids, and viral hemorrhagic fevers can be transmitted by these materials. used sharps should be disposed of into suitable containers (proper sharps boxes are ideal but old metal containers such as coffee or milk powder tins are adequate). medical waste should ideally be burned in an incinerator. this should be close to the clinic or hospital but downwind of the prevailing wind. a -l oil drum can be used for this purpose with a metal grate half way up and a hole at the bottom to allow in air and for the removal of ash. larger-scale and more permanent incinerators can be constructed if necessary. burning pits can be used in emergency. if burning is not possible items should be buried at least . m deep. this is more suitable than burning for large items of human tissue such as amputated legs. ensure there is no risk of groundwater contamination. a few others, such as malaria and other vector-borne diseases (e.g., typhus and leishmaniasis), are also likely to occur but are region specific. tb and hiv or aids can also cause major problems in the longer term this is a complex process involving not just considerations of infection risk but also legal, sociocultural, and psychological factors. there are a number of specialist publications which can be of help. after almost every natural disaster, fear of disease has encouraged authorities to dispose rapidly of the bodies of the dead, often without identifying them, and this sometimes seems almost to take precedence over dealing with the living. however, in sudden impact disasters (such as the indian ocean tsunami in ), the pattern and incidence of disease found in the dead will generally reflect those in the living. the situation is much the same in wars and other long drawn out disasters, although these may affect disease patterns and create vulnerable groups. in fact dead bodies pose little risk to health (with some exceptions listed below) since few pathogenic microorganisms survive long after the death of their host. the diseased living are far more dangerous. the decay of cadavers is due mainly to organisms they already contain and these are not pathogenic. those most at risk are those handling the deceased, not the community. the most likely risks to them are as follows: mortuary facilities may need to be provided where the dead can be preserved until appropriate legal proceedings have been undertaken and where relatives, etc., may easily attend to identify and claim the deceased. cold stores and refrigerated vehicles can be used as temporary mass mortuary facilities. alternatively such facilities can be provided in buildings, huts, or tented structures, but refrigeration will be needed. the dead must always be treated with dignity and respect. as far as possible the appropriate customs of the local population or the group to which the deceased belonged should be observed. if the dead have to be buried in mass graves then the layout of the cemetery must be carefully mapped to facilitate exhumation if needed. when an individual may have died of a particularly dangerous infection, then body bags should be used (and also for damaged cadavers). in general, bodies should be buried rather than cremated (as exhumation for purposes of identification may be needed). bodies should be buried at least . m deep or, if more shallowly, should have earth piled at least m above the ground level and . m to each side of the grave (to prevent access by scavengers and burrowing insects). disinfectants such as chloride of lime should not be used. new burial sites should be at least m from drinking water sources and at least . m above the saturated zone. vaccination programs are an essential part of disease prevention. information about existing vaccination programs must be obtained during the assessment process and this should include information from external assessors (e.g., who, unicef, ngos) as to the effectiveness of the vaccination programs that have been undertaken in the past. it cannot be assumed that simply because children have received vaccines that these vaccines were effective. measles kills large number of children in developing countries and is one of the greatest causes of morbidity and mortality in children in refugee and idp camps. mass vaccination of children between the ages of months and years should be an absolute priority during the first week of activity in humanitarian situations and can be conducted with the distribution of vitamin a. a system for maintaining measles immunization must be established once the target population has been covered adequately in the initial campaign. this is necessary to ensure that children who may have been missed in the original campaign, children reaching the age of months, and children first vaccinated at the age of - months who must receive a second dose at months of age are all covered. some of the children vaccinated during such a mass campaign may have been vaccinated before. this does not matter and a second dose will have no adverse effect. it is essential to ensure full coverage against measles in the population. other epi vaccinations for children are not generally included in the emergency phase because they can only prevent a minor proportion of the overall morbidity and mortality at that stage. however, should specific outbreaks occur then the appropriate vaccine should be considered as a control measure. vaccination programs require the following: • appropriate types of vaccines. • appropriate amounts of these vaccines. • equipment (needles, syringes, sterilization equipment, sharps disposal). emergency immunization kits, including cold chain equipment, are available from a number of sources, including unicef and some ngos (e.g. msf). • logistics (transport, cold chain). • staff: a vaccination team may be quite large. it must include the following personnel: -a supervisor. -logistics staff. -staff to prepare and administer vaccines. -record keepers. -security staff (to maintain order and control crowds) may also be needed. maintenance of the cold chain is particularly important. this is the system of transporting and storing vaccines within a suitable temperature range from the point of manufacture to the point of administration. the effectiveness of vaccines can be reduced or lost if they are allowed to get too cold, too hot, or are exposed to direct sunlight or fluorescent light. careful note should be taken of the conditions needed to transport different vaccines because these can vary. the essential cold chain equipment needed to transport and store vaccines within a consistent safe temperature range includes the following: • dedicated refrigerators for storing vaccines and freezers for ice packs (fridges and freezers powered by gas or kerosene are available as alternatives to electric machines, and solar-powered fridge/freezer combinations specially designed for vaccine storage are also available) • a suitable thermometer and a chart for recording daily temperature readings if possible, vaccines should be stored in their original packaging because removing the packaging exposes them to room temperature and light. check the temperature to ensure the vaccines have not been exposed to temperatures outside the normal storage ranges for those vaccines (see table . ). max. storage time at the different levels: primary, months; region, months; district, month; health center, month; health post, daily usemax. month diluents must never be frozen. freeze-dried vaccines supplied packed with diluent must be stored between + and + °c. diluents supplied separately should be kept between + and + °c vaccines must be kept at the correct temperature since all are sensitive to heat and cold to some extent. all freeze-dried vaccines become much more heat-sensitive after they have been reconstituted. vaccines sensitive to cold will lose potency if exposed to temperatures lower than optimal for their storage, particularly if they are frozen. some vaccines (bcg, measles, mr, mmr, and rubella vaccines) are also sensitive to strong light and must always be protected against sunlight or fluorescent (neon) light. these vaccines are usually supplied in dark brown glass vials, which give them some protection against light damage, but they must still be covered and protected from strong light at all times. only vaccine stocks that are fit for use should be kept in the vaccine cold chain. expired or heat-damaged vials should be removed from cold storage. if unusable vaccines need to be kept for a period before disposal (e.g., until completion of accounting or auditing procedures) they should be kept outside the cold chain, separated from all usable stocks and carefully labelled to avoid mistaken use. diluents for vaccines are less sensitive to storage temperatures than are the vaccines with which they are used (although they must be kept cool), but may be kept in the cold chain between + and + °c if space permits. however, diluent vials must never be frozen (kept in a freezer or in contact with any frozen surface) as the vial may crack and become contaminated. when vaccines are reconstituted, the diluent should be at same temperature as the vaccine, so sufficient diluent for daily needs should be kept in the cold chain at the point of vaccine use (health center or vaccination post). at other levels of the cold chain (central, provincial, or district stores) it is only necessary to keep any diluent in the cold chain if it is planned to use it within the next h. freeze-dried vaccines and their diluents should always be distributed together in matching quantities. although the diluents do not need to be kept in the cold chain (unless needed for reconstituting vaccines within the next h), they must travel with the vaccine at all times, and must always be of the correct type, and from the same manufacturer as the vaccine that they are accompanying. each vaccine requires a specific diluent, and therefore, diluents are not interchangeable (for example, diluent made for measles vaccine must not be used for reconstituting bcg, yellow fever, or any other type of vaccine). likewise, diluent made by one manufacturer for use with a certain vaccine cannot be used for reconstituting the same type of vaccine produced by another manufacturer. some combination vaccines comprise a freeze-dried component (such as hib) which is designed to be reconstituted by a liquid vaccine (such as dtp or dtp-hepb liquid vaccine) instead of a normal diluent. for such combination vaccines, it is again vital that only vaccines manufactured and licensed for this purpose are combined. note also that for combination vaccines where the diluent is itself a vaccine, all components must now be kept in the cold chain between + and + °c at all times. as for all other freeze-dried vaccines, it is also essential that the "diluent" travels with the vaccine at all times. the effectiveness of a vaccination program will need to be assessed. the program can be evaluated both by routinely collected data and, if necessary, by a survey of vaccination coverage. routine data on coverage is obtained by comparing the numbers vaccinated with the estimated size of the target population (and clearly depends on accurate assessment of the latter). a coverage survey requires the use of a statistical technique called a two-stage cluster survey details of which can be found in the appropriate who/epi documents. information about the effectiveness of the campaign should be obtained from routine surveillance of communicable disease. if, for example, large number of measles cases continue to occur, or there is an outbreak, then data on coverage should be reexamined. if this is shown to be good (over %) then the efficacy of the vaccine must be suspected. if the field efficacy is below the theoretical value % (for measles vaccine -data on efficacy of other vaccines can be obtained online) then possible causes of a breakdown in the vaccination program must be investigated (failure of the cold chain, poorly respected vaccination schedule). methods for measuring vaccine efficacy can be found in the who/epi literature. mass chemoprophylaxis for bacterial infections such as cholera and meningitis is not usually recommended except on a small scale (for example, the use of rifampicin may be considered to prevent the spread of meningococcal meningitis among immediate contacts of a case), but the difficulties of overseeing such activities and the risks of the development of antibiotic resistance outweigh any benefits that might be gained. the use of chemoprophylaxis for malaria must be undertaken with care. it may be indicated for vulnerable groups of refugees/idps (for example, children and pregnant women) arriving in an endemic area, particularly if they come from a nonmalarious area, but care must be taken to provide drugs to which the local strains of malaria are sensitive. the spread of resistance means that many of the standard drugs are ineffective and the replacements are both costly and may have unwanted side effects. public health education and information activities play a vital role in disease prevention. vaccination programs will not work unless there is acceptance by the public of the necessity for such programs. individuals must be informed as to why these programs are necessary and also where and when they need to take their children for vaccination. such activities are also essential to inform people about particular health programs (for example, feeding programs or vector control programs) and about the steps they can take to protect their health and that of their families (e.g., good hygiene). information can be propagated in many ways: staff who are trained in this type of activity therefore play a key role in disease prevention. heath education also requires transport and equipment (such as video or film projectors, screens, generators, blackboards, etc.). details of the treatment of individuals for various infectious diseases and the facilities needed are covered elsewhere in this book and in many textbooks covering disasters and disease response. in terms of the population aspects of the treatment of disease, important requirements are to ensure that there are • appropriate laboratories (microbiological, parasitological, hematological, biochemical) available to confirm diagnoses and monitor treatment. • adequate supplies of appropriate antimicrobial agents available and the facilities to transport these, store, and distribute them under appropriate conditions (e.g., controlled temperature), together with relevant instruction for use. the provision of laboratory facilities in emergencies is usually limited to basic tests such as those for malaria. more advanced tests, including identification of microorganisms and the determination of antimicrobial sensitivities, require more sophisticated facilities. these may be available in the affected country but are unlikely to be operating in the disaster-affected area. it is more likely that specimens will have to be transported to laboratories abroad. collection of specimens requires appropriate equipment. this will include items such as swabs, transport media, needles, syringes, or vacum sampling systems for blood sampling, different blood collection bottles (with and without anticoagulants) and other sterile specimen tubes, and containers for faeces and urine. transporting specimens must be done safely, and packing specimens for shipment requiring specially trained personnel. treatment of disease requires good supplies of appropriate antimicrobial agents. it is important to ensure that the agents chosen are suitable for use in the area. it is common for doctors in affected areas to ask for the latest therapeutic agents. however, these agents, although effective, are often expensive and not part of the normal treatment programs in the region. the local doctors may not therefore be familiar with the use of these agents, nor may laboratories be capable of monitoring their use. it is better to use funds, which are often limited, to supply larger amounts of older (generic) agents. one caveat is the possibility that regular use may have allowed resistance to certain agents to develop in a country. data on this may be available from local surveillance records. antimicrobials should always be supplied with relevant guidelines in a language that can be understood locally. if local laboratories are unable to test microbes for resistance to antimicrobials, isolates or specimens should be sent as soon as possible to appropriate reference laboratories for testing. outbreaks of communicable disease may occur before preventive measures can take effect or because the measures are in some way inadequate or fail. an epidemic is generally defined as the occurrence in a population or region of a number of cases of a given disease in excess of normal expectancy. an outbreak is an epidemic limited to a small area (a town, village, or camp). the term alert threshold is used to define the point at which the possibility of an epidemic or outbreak needs to be considered and preparedness checked. the areas where vaccination campaigns are a priority need to be identified and campaigns started. the term epidemic (outbreak) threshold is used to define the point at which an urgent response is required. this will vary depending upon the disease involved (infectiousness, local endemicity, transmission mechanisms) and can be as low as a single case. infections where a single case represents a potential outbreak include the following: infections where the threshold is set higher, usually based on long-term collection of data, and will vary from location to location, include the following: • human african trypanosomiasis • visceral leishmaniasis a surveillance system that is functioning well should pick up the signs that an outbreak or epidemic is developing and should therefore allow time for measures to be introduced that will prevent or limit the scale of the event. however, this may not always work and it is essential therefore that plans are made to combat outbreaks or epidemics. in addition to the establishment of surveillance, outbreak preparation involves the following: • preparing an epidemic/outbreak response plan for different diseases covering the resources needed, the types of staff and their skills that may be needed and defining specific control measures. • ensuring that standard treatment protocols are available to all health facilities and health workers and that staff are properly trained. • stockpiling essential supplies. this includes supplies for treatment, for taking and shipping samples, other items to restock existing health facilities and the means to provide emergency health facilities if required. • identifying appropriate laboratories to confirm cases and support patient management, make arrangements for these laboratories to accept and test specimens in an emergency, and set up a system to ship specimens to the laboratory. • identifying emergency sources of vaccines for vaccine-preventable diseases and make arrangements for emergency purchase and shipment. ensure that vaccination supplies (needles, syringes, etc.) are adequate. make sure the cold chain can be maintained. • identifying sources for other supplies, including antimicrobials, and make arrangements for emergency purchase and shipment. if the number of reported cases is rising, is this in excess of the expected number? ideally work with rates rather than numbers (see above) because (for example) the number of cases in a refugee camp could increase if the number of people in the camp increases without an outbreak occurring. verify the diagnosis (laboratory confirmation) and search for links between cases (time and place). laboratory confirmation requires the collection of appropriate specimens and their transport to an appropriate laboratory. in the case of a limited outbreak this team should be set up by the lead agency with membership from other relevant organizations, including moh, who, other un organizations, ngos, etc. in the case of an epidemic the moh will probably take the lead or may ask who or another un agency to do so. the team will need to include a coordinator, and specialists from the various disciplines needed to control the outbreak. this may include health workers, laboratory staff, water and sanitation, vector control, and health education specialists, representatives of the moh or other local health authorities, representatives of local utilities (e.g., water supply), representatives of the police and/or military, and representatives of the local community. this team should meet at least once a day to review the situation and define the necessary responses. it has additional responsibilities, including implementing the response plan, overseeing the daily activities of the responders, ensuring that treatment protocols are followed, identifying resources (both material and human) to manage the outbreak and obtaining these as necessary, and coordinating with local, national, and international authorities as required. the team should also act as the point of contact for the media. a media liaison officer should be appointed and all media contact should be through this individual. this will allow team members to refer media representatives to a central point and reduce interference with their activities. it will also ensure that a consistent message based on the most complete data is given to the media. the appropriate national authorities should be informed of the outbreak. in addition to their responsibilities to their own population and to any refugees within their borders, they have a responsibility under the revised international health regulations ( ) to report outbreaks of certain diseases. these include four diseases regarded as public-health emergencies of international concern: • smallpox • polio (wild-type) in some cases, member states must report outbreaks of additional diseases: cholera, pneumonic plague, yellow fever, viral hemorrhagic fever, and west nile fever, and other diseases that are of special national or regional concern (e.g., dengue fever, rift valley fever, and meningococcal disease). once the diagnosis has been confirmed and the causative organism identified, then there are a number of steps that must be taken in addition to continuing to treat those affected: • produce a case definition for the outbreak. this is primarily a surveillance tool that will reduce the inclusion of cases that are not part of the outbreak and prevent dilution of the focus and activities of the main control effort. • collect and analyze descriptive data by time, person, and place (time and date of onset, individual characteristics of those affected -age, sex, occupation, etc., location of cases). plot the distribution of the cases on a map (can help locate source(s) of an outbreak and determine spread) and plot outbreak curves (which will help estimates of how the outbreak is evolving). • determine the population that is at risk. • determine the number of cases and the size of the affected population. calculate the attack rate. • formulate hypotheses for the pathogen about the possible source and routes of transmission. • conduct detailed epidemiological investigations to identify modes of transmission, vectors/carriers, risk factors). • report results and make recommendations for action. the two main statistical tools used to investigate outbreaks are as follows: • case-control studies in which the frequency of an attribute of the disease in individuals with the disease is compared to the same attribute in individuals without the disease matched in terms of age, sex, and location (the control group) • cohort studies in which the frequency of attributes of a disease is compared in members of a group (for example, those using a particular feeding center) who do or do not show symptoms however the design and methods involved in such studies are often too complex for the austere environment of conflict and disaster. • implement prevention and control measures specific to the disease organism (e.g., clean water, personal hygiene for diarrheal disease) • prevent infection (e.g., by vaccination programs) • prevent exposure (e.g., isolate cases or at the least provide a special treatment ward or wards) • evaluate the outbreak detection and response -were they appropriate, timely, and effective? • change/modify policies and preparedness to deal with outbreaks if required • what activities are needed to prevent similar outbreaks in the future (e.g., improved vaccination programs, new water treatment facilities, public health education, etc.)? • produce and disseminate an outbreak report. the report should include details of the outbreak, including the following: -cause -duration, location, and persons involved -cumulative attack rate (number of cases/exposed population) -incidence rate -case fatality rate -vaccine efficacy (if relevant) (no. of unvaccinated ill − no. of vaccinated ill/no. of unvaccinated ill) -proportion of vaccine-preventable cases (no. of vaccine-preventable cases/no. of cases) -recommendations this is an easy-to-use tool which is of great value for handling epidemiological data and for organizing study designs and results, which can be downloaded free of charge from the internet. it is produced by the centers for disease control (atlanta) and is a series of microcomputer programs which can be used both for surveillance and for outbreak investigation and includes features used by epidemiologists in statistical programs, such as sas or spss, and database programs such as dbase. public health action in emergencies caused by epidemics. geneva: who, . cdc atlanta. case definitions for infectious conditions under public health surveillance updated guidelines for evaluating public health surveillance systems epidemiology for the uninitiated communicable disease control in emergencies -a field manual last jm (ed). dictionary of epidemiology medicins sans frontieres. refugee health -an approach to emergency situations geneva: international committee of the red cross sphere project. humanitarian charter and minimum standards in disaster response. geneva: the sphere project key: cord- - qwbkg o authors: hoddle, mark s. title: biological control of vertebrate pests date: - - journal: handbook of biological control doi: . /b - - / - sha: doc_id: cord_uid: qwbkg o nan several species of vertebrates, especially mammals, have been successful invaders and colonizers of new territories, in particular, insular island ecosystems. others have exhibited high environmental tolerance and adaptability after careful and repeated introductions to new locales by humans. following establishment, several vertebrate species have become important pests. these pests harm agricultural systems by damaging agricultural lands [e.g., rabbits (oryctolagus cuniculus linnaeus) in australia and new zealand], by attacking crops [e.g., european starlings (sturnus vulgaris linnaeus) in the united states], and by acting as sources for communicable diseases [e.g., brushtail possums, (trichosurus vulpecula kerr) , are reservoirs for bovine tuberculosis (mycobacterium bovis karlson and lessel) in new zealand]. other pest vertebrates damage natural systems by threatening the continued existence of endangered flora [e.g., goats (capra hircus linnaeus) on the galapagos islands] and fauna [e.g., brown tree snake (boiga irregularis { merrem }) on guam], and by adversely affecting wilderness areas by changing ecosystem functions and diversity (vitousek et al., ) . the continued relocation of vertebrates exacerbates the ongoing problem of global homogenization of biota (lodge, ) . movement of particular vertebrates into areas where they had not previously existed has, in some instances, occurred naturally without human intervention [e.g., the passerine bird (zosterops lateralis { latham }) arrived in new zealand unassisted from australia]. the vast majority of vertebrate translocations have been human assisted. accidental introduction has occurred as a consequence of human transportation [e.g., brown tree snakes, mice (mus musculus lin-naeus) , and rats such as rattus rattus linnaeus and r. norvegicus berkenhout) ]. some releases have been intentional (but illegal) to serve self-centered private interests [e.g., monk parakeets (myiopsitta monachus { boddaert }) in new york, florida, and texas]. other species have been legitimately introduced to procure public benefit by providing: ( ) new agricultural products [e.g., european wild boars (sus scrofa linnaeus); sheep (ovis aries linnaeus); cows (bos taurus linnaeus), goats and rabbits for meat, and brushtail possums for fur in new zealand], ( ) recreation [e.g., red deer (cervus elaphus linnaeus), fallow deer (dama dama linnaeus), and trout (salmo trutta linnaeus and s. gairdneri richardson) in new zealand]; ( ) companionship [e.g., cats (felis domesticus linnaeus) and dogs (canis familiaris linnaeus)]; or ( ) biological control agents [e.g., the european fox (vulpes vulpes linnaeus), stoats (mustela erminea linnaeus), weasels (m. nivalis linnaeus) , and ferrets (m. putorius furo linnaeus) for the control of rabbits in australia or new zealand; cane toads chemical and cultural control of vertebrate pests is expensive and nonsustainable, and at best provides a temporary local solution to problems (hone, ; williams & moore, ) . biological control of vertebrates, a potentially less expensive and self-sustaining method of population suppression, has focused primarily on mammalian pests. predators, parasites, and pathogens specific to mammals with two notable exceptions (the myxoma and calici viruses that infect rabbits) have failed to provide satisfac-tory control (shelford, ; howard, ; davis et al., ; wood, ; smith & remington, ; whisson, ) . historical records indicate that the majority of attempts at vertebrate biological control have been ad hoc efforts and not the product of careful studies designed to elucidate factors and conditions likely to affect the impact of natural enemy introductions on pest populations. furthermore, failure of biological control of vertebrates by predatory vertebrates has compounded problems associated with exotic vertebrates because control attempts result in addition of new species that cause biological and conservation problems. the level of control achieved by natural enemies is dependent on ratios of natality to mortality of control agents and their host species (davis et al., ) . for vertebrates these ratios are affected by many factors: advanced learning; social, territorial, and breeding behaviors; chemical, physical, and immunological defenses; temporal and spatial escape strategies; and genetic selection in both natural enemy and host populations for persistent coexistence. these complex interrelated factors, coupled with opportunistic feeding habits, have made vertebrate pests difficult targets for biological control with natural enemies. advances in understanding of mammalian fertilization biology have provided molecular biologists with necessary information to develop and investigate the concept of immunocontraception for vertebrate pest control. immunocontraception utilizes genetically modified pathogens that express surface proteins from the target pest's egg or sperm to induce an immune response in the host. antibodies then attack gametes in the host's reproductive tract causing sterilization (tyndale-biscoe, b . computer models indicate that immunocontraception may provide long-term control of vertebrate pests because genetically modified pathogens reduce net reproductive rates without killing hosts (barlow, (barlow, , . in this chapter, i discuss attributes that have aided vertebrate establishment; damage resulting from colonization and uncontrolled population growth; biological control of mammalian pest species with predators, parasites, and pathogens; and future directions that biological control research for vertebrates is taking with genetically engineered microorganisms. permissive to successful introductions of new species. e ton's ( ) predictions have been substantiated in part by paleobiological reconstructions of invasions between newly joined communities (vermeiji, ) and by mathematical modeling describing multi-species interactions in communities (macarthur, ; case, ) . isolated oceanic islands (e.g., new zealand), and insular continents and habitats (e.g., australia and lakes) often have a low diversity of native species. such environments have typically experienced little immigration and are susceptible to invasion by vertebrates (brown, ) . stable, speciose communities with high levels of interspecific competition appear to resist invasion by new species and are sources of successful colonists into less speciose or disturbed communities (macarthur, ; brown, ; lodge ) . this phenomenon has produced asymmetrical patterns of colonization, with successful vertebrate invaders usually being native to continents or extensive nonisolated habitats within continents with more diverse biotas (brown, ; vermeiji, ) . continental herbivores and predators have been very successful in establishing self-sustaining populations in insular habitats, in part because such habitats often lack large generalist vertebrates and essentially have just two trophic levels, producers and decomposers (if specialist herbivores and their predators are excluded) (vitousek, ) . niches equivalent to those on the mainland are largely unoccupied (brown, ) . insular ecosystems therefore often appear to readily accommodate generalist herbivores and predators, perhaps because of low levels of competition for resources that are often inadequately defended chemically or physically (vitousek, ; vermeij, ; bowen & van vuren, ) . organisms from insular habitats that have not coevolved closely with predators or herbivores lack life history features that deter attack or permit survival despite high mortality from predation or herbivory (bowen & van vuren, ) . lack of such biological attributes may increase the competitive advantage of exotics (case, ; coblentz, ; vitousek, ) . introduced vertebrates can also be extremely disruptive in continental regions when habitat disturbance by urbanization or agriculture occurs. european wild boars have detrimental effects on gray beech forests in the great smoky mountains in the southeast united states. habitat disturbance-through pig rooting, trampling, and browsing-and human removal of predators (pumas and wolves) aided pig establishment and spread in this area (bratton, ; singer et al., ; vitousek, ) . communities vary in their ability to accommodate the establishment and proliferation of new species (primack, ) . elton ( ) suggested that species-poor communities (e.g., islands) or highly disturbed habitats are more although there are well-recognized exceptions to general rules that characterize successful vertebrate colonists (ehrlick, ; williamson & fitter, b) , species that establish self-sustaining populations outside their native range typically exhibit some of the following general characters: ( ) short generation times, ( ) high dispersal rates, ( ) high tolerance for varying geographic and climatic conditions, ( )polyphagy, ( ) low attack rates from upper trophic level organisms, and ( ) human commensalism (ehrlich, (ehrlich, , lodge, ; williamson & fitter, a) . the assumption of a high intrinsic rate of increase is generally unnecessary for establishment (ehrlich, ; lodge, ) , although it is important for the establishment of some exotic bird species (veltman et al., ) . the spread of the european rabbit in australia and new zealand, countries that both historically lacked significant eutherian mammal fauna, illustrates some of the preceding points. the european rabbit originated in spain and portugal (corbet, ) and spread through most of europe over years ago following deforestation by humans for agriculture and overgrazing by livestock. animals reared in captivity were carried through europe in advance of naturally spreading populations (flux, ) . the spread of the european rabbit throughout australia following its introduction in varied from km/year to approximately km/year. rate of spread was fastest across dry savannas where conditions were most similar to mediterranean climates and slowest through woodlands (myers et al., ) . in australia, habitat alteration by humans such as conversion of land to pasture, overgrazing of rangelands, and predator eradication [e.g., dingos (canis familiaris dingo meyer)] aided rabbit survivorship and spread. rabbits are polyphagous and feed on grasses and browse shrubs. during severe food and water shortages, bark, fallen leaves, seed pods, tree roots, and termites are consumed (myers et al., ) . rabbits are highly fecund and exhibit rapid population growth under good conditions. individual female rabbits to months of age can produce litters averaging to young, and with abundant food to offspring per year are produced (gibb & williams, ) . behavioral adaptability, sociality, and territoriality, in addition to use of elaborate underground warrens, have also aided rabbit proliferation in marginal habitats (myers et al., ) . assistance in establishment some of the first introductions of exotic vertebrates were those commensal with humans as they colonized new areas. among well-documented early human introductions are dingoes in australia (brown, ) and polynesian rats [rattus exulans (peale)] on pacific islands (roberts et al., ) . as early europeans explored the planet, other commensal species such as r. rattus, r. norvegicus, and mus musculus expanded their geographic range without deliberate human assistance and are now cosmopolitan in distribution (brown, ) . not all vertebrate pests cohabitat with or are associated with human disturbance of the environment. red deer and feral cats, for example, inhabit much of new zealand's pristine habitats with no human management. most vertebrate translocations fail even with human assistance. failure of exotics to establish may depend on life history parameters, responses to abiotic factors, inability to outcompete native species for resources or enemy free space, or chance (cornell & hawkins, ) . deliberate releases of exotic birds have establishment rates of around to % (veltman et al., ) . establishment estimates for intentional vertebrate releases are biased because successes are more often recorded than failures (ehrlich, ; veltman et al., ) . the amount of effort directed toward introduction is an important variable affecting successful colonization by vertebrates, and establishment rates increase with high levels of management and numbers of individuals released (ehrlick, ; griffith et al., ; williamson & fitter, b; veltman et al., ) . in contrast, organisms that are casually introduced into new areas have much lower probabilities of establishing and proliferating. this phenomenon is expressed in the tens rule, a statistical characterization of probability outcomes for different levels of invasion success (williamson & fitter, a , b . for a variety of plants and animals, a general rule holds that in species imported (i.e., brought into new areas intentionally or accidentally) appear in the wild, in of those now found in the wild become established, and that in of those established with self-sustaining populations become pests (williamson & fitter, b) . following establishment, proliferation, and rise to pest status, control of exotic vertebrates is often prompted by economic, environmental, or conservation concerns. several control strategies may be pursued, the most common being chemical control (e.g., poisoning) and cultural control (e.g., trapping, fencing, and shooting). the least used option has been biological control. chemical and cultural control of vertebrate pests has been covered by hone ( ) and williams and moore ( ) . biological control is the intentional use of populations of upper trophic level organisms (e.g., predators, parasites, and pathogens) commonly referred to as natural enemies to suppress populations of pests to lower densities than would occur in the absence of natural enemies (debach, ; van driesche & bellows, ) . biological control programs for vertebrates have employed all three classes of natural enemies: predators, parasites, and pathogens. in contrast to weeds and pestiferous arthropods, however, biological control as a population suppression tactic for management of vertebrate pests has historically received much less attention. predators of vertebrates in the few instances they have been used have not been particularly successful. some vertebrate predator introductions also had severe impacts on nontarget organisms. consequently, early unpromising results discouraged intensive development of this technology (howard, ; davis et al., ; wood, ) . there is a need for increased effort using biological control agents against vertebrates, especially where resistance to toxins has developed, or behavior and terrain makes chemical and cultural control difficult and expensive (wood, ; bloomer & bester, ) . biological control should be fostered internationally because many countries experience similar problems (e.g., rabbits are agricultural pests in argentina, australia, chile, europe, and new zealand; rats, cats, and dogs attack endangered faunas on many oceanic islands; feral pigs and goats in new zealand, australia, and the united states degrade habitat and threaten endangered flora). biological control can be aided by the establishment of institutions to help coordinate regional and international research activities. for example, in , the australian federal government supported the creation of the cooperative research center for biological control of vertebrate pest populations (also known as the vertebrate biocontrol center), an unincorporated collaborative venture between state and federal organizations with international cooperators (anonymous, a) . the principle research goal of this institution is population suppression of noxious vertebrate species by regulating reproductive rates (tyndale-biscoe, a). a fundamental issue that has important implications for biological control is understanding the regulatory effects predators have on prey populations. determining impact of introduced predators on pest and nontarget populations is becoming increasingly more important as public awareness of potential nontarget impacts increases and the impact of past introductions on nontarget organisms has become clearer (howarth, ; van driesche & hoddle, ) . introductions of vertebrate predators as biological control agents against vertebrates have in some instances had disastrous impacts on nontarget wildlife, especially insular communities that have lacked an evolutionary history with generalist predators (case, ) . an example is the impact the small indian mongoose on native rail populations in hawaii following its release in the s for rat control (loope et al., ) . the mongoose has little demonstrable effect on rats (cagne, ) and mongoose populations are now poisoned to protect native birds (loope et al., ) . exotic predators may enhance the success of introduced pest species by moderating the competitive impact of natives on introduced pests should predators reduce densities of native species (case, ) . on the other hand, there is very good evidence that under certain circumstances introduced exotic predators can regulate target vertebrate pests. in such cases, predator efficacy may be affected by ecosystem complexity; by influence of such extrinsic factors as weather, disease, or human intervention on pest population growth; and by the availability of alternative food sources to sustain predators when pest populations are low. in simple ecosystems such as islands, establishment of reproducing predator populations can result in the extinction of target pests. in the absence of alternative prey, releases of cats for rabbit control on berlinger island near portugal by a lighthouse keeper resulted in the eradication of the rabbits, and subsequently cats died from starvation (elton, ) . in complex communities, alternate prey may be taken when primary prey populations are low for prolonged periods, as is the case for some microtine rodent species in europe. european rodent populations exhibit fluctuations in size as a response to variation in food availability. these fluctuations are also influenced by predation. population cycles are not observed in southern hemisphere countries where european pests and predators have been transferred (korpim~iki & krebs, ; sinclair, ) . rabbit populations in australia and new zealand are maintained at low levels by introduced predators, but regulation only occurs after pest numbers have been reduced by other means. poisoning programs in new zealand in the s and s substantially reduced rabbit densities and populations were maintained at low levels by introduced predators, in particular, ferrets and cats (newsome, ) . similarly in australia, european foxes and cats maintain rabbit populations at low densities following population crashes caused by prolonged hot summers that reduce forage and browse (newsome et al., ; newsome, ) . mouse populations are regulated in a similar fashion by predators (raptors and foxes) in australia (sinclair et al., ) . introduction of two foxes dusicyon culpaeus (molina) and d. griseus (gray) native to mainland chile onto the chilean side of tierra del fuego island regulated rabbit populations after rabbit densities were substantially reduced by the myxoma virus (jaksic & yhfiez, ) . the suppressive action of predators on rabbits in australia has been demonstrated through predator removal experiments [referred to as perturbation experiments by sinclair, ( ) ] in which european foxes and cats were shot from four-wheel drive vehicles at night. removal of predators resulted in rapid rabbit population growth compared with rabbit densities in control plots in which predators were not removed (newsome et al., ) . the "predator pit" first conceptualized by may ( ) describes rabbit regulation in australia and new zealand by generalist predators. the model suggests that once prey populations fall below certain densities (i.e., because of culling or disease) predators can prevent recovery to higher levels. generalist predators achieve this by maintaining relatively high numbers by attacking alternate prey species, and low but persistent levels of predation on species in the pit prevents pest populations from outbreaking. for the rabbit-fox system in australia, a predator pit operates at densities of to rabbits per kilometer of linear transect. below these densities foxes utilize alternate food sources (e.g., native animals) and above this critical density rabbit populations escape regulation by predators (newsome, ) . in new zealand, rabbits are contained in the pit by cats and ferrets when densities are . rabbits per hectare (barlow & wratten, ) . the effect of predators on long-term population dynamics of alternate prey species is generally difficult to disentangle from confounding effects of habitat degradation and competition for food and breeding sites from other introduced species (pech et al., ) . foxes regulate mice and rabbits through positive density dependence at low prey densities. increasing pest densities during outbreaks results in inverse density-dependent predation and type iii functional responses (sinclair et al., ; pech et al., ) . rabbit and mouse populations escape predator regulation when favorable weather provides good breeding conditions, or when predators are controlled by shooting or poisoning (newsome, ; sinclair et al., ; pech et al., ) . predator control may be necessary for lifestock protection or for conservation of endangered wildlife and when implemented resurgence of pest populations occurs (newsome et al., ; newsome, ) . predator numbers may increase when primary prey (e.g., rabbits) are abundant. predation by abundant predators on secondary prey (e.g., native animals) result, leading to declines in secondary prey density. under such circumstances native prey species may only persist in refugia or in areas with artificially reduced predator pressure (pech et al., ) . altematively, declining densities of a primary pest prey species (either through management or disease) can intensify predator attacks on nontarget organisms. therefore, when conservation of endangered natives is a concern, culling of predators may be undertaken either concurrently with the decline in prey density or in anticipation of such a decline (grant norbury, personal communication, ) . in such situations an integrated approach to managing vertebrate pests and their predators is necessary (newsome, ) . predator efficacy can be enhanced either through habitat modification or resource provisioning. cats can maintain rat and mouse populations around farm buildings below environmental carrying capacity as long as they are provisioned with additional food (e.g., milk). dietary supplementation prevents rodent extermination and the subsequent extinction of cats. sustaining a cat population prevents uncontrolled invasions by rodents and low pest densities are maintained (elton, ) . provision of nesting boxes for barn owls (tyto alba javanica) reduces crop damage by rats in malaysian oil palm plantations; rodenticide use declined, and in some instances use was eliminated (wahid et al., ) . changes in management practices can improve predator efficacy. rodent control by tyto alba (scopoli) in pinus radiata don plantations in chile was enhanced by clearing -m wide strips between trees (for owls to maneuver in while in flight) and construction of perches in forests (for resting and surveillance). bam owl numbers and predation rates on rodents increased following habitat modification (mufioz & murfa, ) . under increased predation pressure, rodents will modify foraging behaviors by reducing activity when owls are flying or making hunger calls (abramsky et al., ) . learning in this manner produces behavioral adaptations because of strong selection pressures to minimize predation risks on pest populations (davis et al., ) . parasites or macroparasites (e.g., helminths, lice, ticks, fleas, and other metazoans) do not typically kill their hosts as a prerequisite for successful development as insect parasitoids do. they tend to be enzootic (i.e., remain at fairly constant levels through time) and usually must pass through a free-living stage to complete an entire life cycle (anderson, ; mccallum, ) . the potential of parasites to regulate vertebrate host populations was first proposed as early as (lack, ) and later was demonstrated theoretically with lotka-voltera models in which parasites increased host mortality rates may, ) . parasites act in a positive density-dependent manner by adversely affecting host survival or reproduction dobson & hudson, ; scott & dobson, ) . host parasite load also affects the ability of individual parasites to grow, reproduce, and survive in definitive hosts; and the severity of density dependence on host and parasite fitness is affected by patterns of parasite distribution in host populations (scott & lewis, ) . helminths, for example, tend to be aggregated within host populations so that few hosts are heavily burdened while most are lightly infected (scott & lewis, ) . density-dependent constraints on parasite survival and reproduction occur in the few heavily infected hosts, and under such conditions, helminth population stability is enhanced . furthermore, parasites with low-to-moderate pathogenicity exert stronger regulatory actions on populations than highly pathogenic species that cause their own extinction by killing hosts before transmission (anderson, ) . parasite regulation of vertebrate populations has been observed under field conditions. botfly (cuterebra grisea coquillett) parasitism of voles [microtus townsendii (bachman)] in vancouver canada, is inversely density dependent; and botfly infestation significantly reduces vole survival, reproduction, and development (boonstra et al., ) . the parasitic helminth trichostrongylus tenuis (cobbold) is the primary agent responsible for long-term population cycles in red grouse [lagopus lagopus scoticus (latham)] inhabiting scottish heathlands (dobson & hudson, ) . the regulatory effect of t. tenuis has been demonstrated by reducing parasite infestations with helminthicides in experimental birds. treated grouse showed increased overwintering survival, clutch sizes, and hatching rates when compared with untreated birds (dobson & hudson, ) . in the laboratory, introduction of the nematode heligmosomoides polygyrus dujardin reduced mice densities by % in comparison with control populations. reduction of nematode transmission rates and elimination of parasites with helminthicides allowed infested mouse populations to increase (scott, ) . although host and parasite densities in this study were higher than those found in nature, the data showed that introduction of a parasite regulated host population abundance. the potential effectiveness of nematodes as biological control agents in field situations has been evaluated for control of the house mouse, an introduced pest in australia (singleton & mc-callum, ; spratt, ) . mouse (mus domesticus) populations erupt every to years in cereal-growing regions of southeastern australia (singleton & mccallum, ; mccallum, ) and economic losses to mouse plagues exceed $ million (australian) (beckman, ; singleton, ) . outbreaks are associated with high autumn rainfalls following prolonged periods of drought that extend the growing season for grasses that set seeds. this high-quality food source increases high mouse survivorship and breeding throughout winter. population crashes occur when food supplies are exhausted (singleton, ) . saunders and giles ( ) suggested that droughts are necessary to remove the regulating effects of natural enemies, and this removal combined with favorable weather conditions permitted mouse numbers to increase rapidly. capillaria hepatica (bancroft), a parasitic nematode that infests mice, is naturally occurring and widely distributed in pestiferous rodents in coastal areas of australia. it is, however, absent in mouse populations in cereal-growing areas . this nematode is unique because it is the only known helminth with a direct life cycle that requires host death for transmission. female nematodes deposit eggs in the host's liver; and these eggs are liberated by predation, cannibalism, or necrophagy with subsequent digestion of infected liver. unembryonated nematode eggs voided after ingestion undergo embryonation to become infective and are probably consumed when mice preen their fur and feet (fig. ) . ground beetles (carabidae) may vector c. hepatica eggs after they have been eaten (mobedi & arfaa, ). firststage larvae emerge from ingested embryonated eggs and move into the liver through the hepatic portal system (wright, ) . nematode infestation significantly reduces natality and numbers of young mice weaned by infected females (mccallum & singleton, ; singleton & mc-callum, ; . capillaria hepatica is associated with introduced rat and mouse species in urban areas, and naturally occurring infections in native australian mammals are rare probably because of the susceptibility of nematode eggs to ultraviolet radiation and desiccation singleton et al., ) . native australian mice and marsupials are susceptible to experimental infection in laboratories . rats (r. norvegicus and r. rattus) are major reservoirs for c. hepatica in urban areas and infestation rates range from to % (childs et al., ; singleton et al., ) . infestation levels are lower in sympatric mice populations ( to %, singleton et al., ) . low rat numbers in cereal-growing regions of australia may be a factor contributing to the nonpersistence of c. hepatica in these areas . infestation of nonrodent mammals by c. hepatica is rare but has occurred in rabbits (gevrey & chirol, ) , dogs (leblanc & fagin, ) , horses (munroe, ) , and humans (pannenbecker et al., ) . human infections can be treated successfully (pereira & franca, ) . exploratory models investigating the impact of c. hepatica on mouse populations indicated that the requirement of host death for parasite transmission is strongly destabilizing. in the absence of resource limitation mouse densities increase similarly to disease-free populations before parasites have an impact and infected populations decline in density (mccallum & singleton, ) . slow regulation of mouse populations occurs because of the need for host death for transmission. consequently, the nematode's life cycle operates on the same time scale as that of its host instead of being orders of magnitude faster, as is the case with other parasites that do not require host death for transmission (mccallum & singleton, ; singleton & mc-callum, ) . the destabilizing influence of c. hepatica on mouse parasitology today, , [ ] [ ] [ ] [ ] populations may contribute to localized host and parasite extinctions. these extinctions, coupled with very low mouse densities in nonoutbreak years, result in population bottlenecks and may explain why nematodes do not persist in regions where mouse outbreaks occur. soil type, temperature, and moisture content do not affect nematode egg survival and embryonation under favorable conditions in outbreak regions (spratt & singleton, ) . outbreak intensity can theoretically be reduced by c. hepatica if populations are inoculated early, preferably year before an outbreak is expected (mccallum, ) . releases of high doses of nematode eggs in the summer or autumn when mouse densities are sufficient to enable high levels of transmission may offer the best chance for successful control (mccallum & singleton, ; mccallum, ) . field experiments in enclosures and with increasing populations of free-ranging mice have failed to demonstrate long-term regulation on mouse population growth with periodic inoculative releases of c. hepatica eggs. unexpected declines in control populations (i.e., populations not treated with nematodes) have to some degree masked the effect of c. hepatica on mice populations singleton et al., ; singleton & chambers, ) . transmission of c. hepatica in treated populations is not density dependent and can occur at low levels for to months. transmission rates show seasonal trends influenced by soil temperatures and increasing aridity singleton & chambers, ) . improved understanding of the influence of factors (such as temperature and rainfall on nematode persistence, survival, and transmission in field situations) and timing of releases of parasite eggs may improve releases of c. hepatica for control of mouse outbreaks (singleton et al., ; singleton & chambers, ) . vertebrate species that successfully colonize new habitats have reduced parasite loads in comparison with mother populations from which they originated (dobson & may, ) . lower infestation levels probably occur because individuals that make up small founding populations either were uninfected or had only a limited subset of the total potential parasite species found in the area of origin, or intermediate hosts required for parasite persistence were absent in the new range. sparrows and starlings, both successful colonizing species from europe, have two to three times fewer parasites in north america compared with populations from which they originated. populations established outside of europe may have benefited from reduced parasite burdens, although there are no quantitative data to indicate that this aided establishment and proliferation (dobson & may, ) . investigating the role of parasites on population dynamics of rabbits in europe with the view for possible introduction into countries where rabbits are pests is also warranted (boag, ) . introduced mammals such as rats, goats, and cats on oceanic islands exhibit depauperate parasite faunas (dobson, ) . fewer parasites coupled with presumed low genetic diversity of small founding populations, and reduced selection pressures for parasite resistance may make these pest vertebrates vulnerable to introduced host-specific parasites. the ideal parasite introduced into a high-density pest population that originated from a small founding population should have low-to-intermediate pathogenicity, because such parasites establish and maintain themselves in populations at lower densities than more pathogenic species do . macroparasites that reduce both host longevity and fecundity may have the potential to cause sustained reductions of host population densities (dobson, ) . low genetic variability among target populations should theoretically enable introduced parasites to become more evenly distributed among hosts, and reduction in parasite aggregation would increase natural-enemy efficacy (dobson & hudson, ) . the possibility of reassociating parasites with vertebrate pests is not limited to mammals and birds. host-specific parasites may have the potential to reduce reproduction and longevity of pest reptile (dobson, ) and amphibian species (freeland, ) . the brown tree snake is the proximate cause of native bird extinctions on guam following its accidental introduction after world war ii on military equipment (pimm, ; savidge, ; jaffe, ; rodda et al., ) . the snake also has caused declines of native reptile and small mammal populations, and enters houses and attacks sleeping human infants (rodda et al., ) . additionally, the brown tree snake has caused eco-nomic losses by adversely affecting domestic animals (e.g., chickens and pets), and high densities of snakes on power lines regularly cause short circuits that interrupt electrical supplies and necessitate repairs. control of the brown tree snake has been attempted through trapping, but the snake's extreme preference for live bait over artificial lures has made this approach impractical (rodda et al., ) . the brown tree snake mnative to eastern indonesia, the solomon islands, new guinea, and northeastern australiambelongs to the family colubridae. it is the only member of this family on guam. there is one native species of snake on guam, the blind snake, rhamphotyphlopys braminus (daudin), which belongs to the family typhlopidae and is the only snake occurring on many islands in the central pacific region (t. fritts, personal communication, ) . the brown tree snake has extended its range and is now established on the previously snake-free island of saipan, and this snake has been intercepted in hawaii; corpus christi, texas, and spain (rodda et al., ) . given the propensity for the brown tree snake to be dispersed to new habitats within cargo loads on planes and ships, the major social, economic, and ecological problems that are caused on islands after colonization, in addition to its distant taxonomic relationship to snakes common to pacific islands, make the brown tree snake an excellent target for biological control. the taxonomic relationship between colubrids and typhlopids may simplify the task and reduce the cost of finding natural enemies unique to the brown tree snake. parasites or pathogens that are host specific just to the family (i.e., colubridae) or genus (i.e., boiga) level may be safe to nontarget snakes (e.g., typhlopids) because these organisms have not evolved the ability to cause disease in distantly related hosts. extreme caution should be exercised when implementing a biological control program against vertebrate pests with parasites. parasites and pathogens can pose major threats to populations of endangered animals (mccallum, ; mccallum & dobson, ) . the susceptibility of nontarget organisms, especially endemic species, to infection by candidate biological control agents should be investigated thoroughly prior to parasite releases. reassociating parasites that preferentially infect a competitively dominant pest species may increase species diversity of invaded communities by reducing the pest's prevalence. in this instance, the natural enemy would assume the position of a keystone parasite (marcogliese & cone, ) . pathogens or microparasites include viruses, bacteria, and protozoans. pathogens tend to be unicellular and exhibit epizootic (i.e., boom or bust) life cycles due to rapid proliferation in hosts (anderson, ; mccallum, ) . the potential of pathogens to regulate vertebrate population densities by reducing the longevity and fecundity of infected hosts has been demonstrated theoretically with mathematical models and by perturbation experiments using vaccines (smith, ) . as with macroparasites, models indicate that microparasites of intermediate pathogenicity are more effective biological control agents (anderson, ) . highly virulent pathogens kill themselves by destroying hosts before they can be transmitted and avirulent strains are not transmitted because they are removed by the immune system. the immune system is theorized as being responsible for maintaining the intermediate virulence of vertebrate microparasites (anita et al., ) . pathogens that are readily transmitted (i.e., microparasites spread by water, air, and vectors) or have high-density host populations are more contagious than those with low transmission rates (i.e., spread is by host-to-host contact) or low host densities (ebert & herre, ) . new associations between pathogens and novel hosts are generally not more harmful than those that have evolved closely with the host. experimental evidence indicates that novel disease-causing organisms are on average less harmful, less infectious, and less fit than the same parasite strain infecting the host it is adapted to (ebert & herre, ) . also, a microparasite's ability to infect and exploit novel hosts decreases with increasing geographic and presumably genetic distance from the host to which the pathogen is adapted (ebert, ) . exceptions do occur, however, and pathogens can have devastating impacts on hosts that have no evolutionary history with the disease organism. an example is the myxoma virus, the causative agent of myxomatosis in european rabbits. the use of this natural enemy against rabbits in australia and europe has been the most thorough biological control program against a vertebrate pest. the myxoma virus is a member of the genus leporipoxvirus (poxviridae) and originated from south america where it was first recognized as an emerging disease of european rabbits in laboratories in montevideo, uruguay, in . infected laboratory rabbits died of a fatal febrile disease that caused tumors on the head and ears. the tumors resembled myxomas (a benign tumor composed of connective tissue and mucous elements) and the disease was subsequently named infectious myxomatosis of rabbits (fenner & marshall, ; fenner & ratcliffe, ; fenner, ) . the indigenous host for myxoma virus in south america is the forest rabbit [sylvilagus brasiliensis (linnaeus)]. unlike its effect on european rabbits, myxoma inoculum injected into forest rabbits caused benign fibromas at the site of inoculation that persisted for many months, although death did not occur. mosquitoes were implicated in vectoring the disease from forest rabbits to european rabbits being bred in south american rabbitries. another leporipox-virus has been isolated in california from the brush rabbit, sylvilagus bachmani (waterhouse), and is closely related to the myxoma virus (fenner & marshall, ; fenner & ratcliffe, ; fenner, ; fenner & ross, ; ross & tittensor, ) . myxoma virus has been used in australia, europe, chile, and argentina for biological control of european rabbits. the virus was first imported into australia from brazil in and but was not released (fenner & ratcliffe, ) . work by australians with the virus began again in the united kingdom in and continued with caged rabbits on wardang island off the south coast of australia. the virus was successfully established on mainland australia in (fenner, ) and within years it had established itself over most of the rabbit's range (fen-ner& ratcliffe, ) . the virus initially had a major impact on the estimated million rabbits and on the damage they caused, reducing population density by to %. efficacy was dependent on climate and rabbit population susceptibility. populations have subsequently increased and stabilized at around million because of myxomatosis. damage attributable to rabbits still amounts to $ million (australian) annually, including both lost agricultural production and cost of control applications (robinson et al., ) . in addition to agricultural losses, rabbits severely affect native flora by eating foliage and inducing wind and water erosion of soils by overgrazing. native fauna are also affected as rabbits out-compete indigenous herbivores and dense rabbit populations sustain exotic predator populations that feed on native animals (gibb & williams, ; myers et al., ; robinson et al., ) . within a few years of the initial panzootic, field isolates of the virus showed less virulence when compared with the original strain that had been released. the original strain killed > % of laboratory rabbits on average . days after infection, while circulating strains caused % mortality after . days. genetic resistance in rabbits was also detected (fenner & marshall, ; fenner & ratcliffe, ) . dual natural selection had occurred, the virus had attenuated, and rabbits had increased in resistance to the disease. mosquitoes have been responsible for vectoring myxoma virus in australia. the european rabbit flea, spilopsylus cuniculi (dale), an important vector in europe, was introduced into australia in and increased the geographic distribution of the disease. this flea did not persist in areas with rainfall < mm. the xeric adapted spanish rabbit flea, xenopsylla cunicularis smit, was introduced in and active redistribution is still ongoing (fenner & ross, ) . new zealand also has inordinate numbers of rabbits, and attempts to establish the myxoma virus from to failed because of inclement weather and a paucity of suit-able arthropod vectors. further attempts at establishment were not undertaken because poisoning programs had reduced rabbits to very low numbers, additional control expenditure was unjustifiable, and the new zealand public was not in favor of using lethal myxoma virus for rabbit control on humanitarian grounds (gibb & williams, ) . until the s, myxomatosis was the only disease known to severely affect rabbit numbers. a second highly contagious viral disease emerged in the mid- s and was accidentally introduced onto mainland australia (o'brien, ) . it is the first pathogenic natural enemy to have established in new zealand for biological control of rabbits. rabbit calicivirus disease (rcd) [also known as rabbit hemorrhagic disease virus (rhdv)] emerged as a fatal disease in in angora rabbits exported from east germany to jiangsu province of china (liu et al., ) . in , the disease appeared in italy where million rabbits were estimated to have died. the disease spread rapidly through rabbit populations in europe reaching the united kingdom in (chasey, ) . the probable mechanism for dispersal in continental europe was the movement of live rabbits and rabbit products. transmission of rcd from france into coastal areas of southeast england is thought to have occurred by wind-borne aerosols containing virus, birds, and transchannel ferry traffic (chasey, ) . outbreaks of rcd occurred in mexico in and (gregg et al., ) and in rrunion island in the indian ocean in . movement of rcd to these areas probably occurred with imports of frozen rabbit carcasses from china because the virus can survive freezing to temperatures of - ~ (chasey, ) . the rcd virus belongs to the caliciviridae and consists of a positive sense, single-stranded rna genome, enclosed by a sculptured capsid composed of multiple copies of a single major protein of kda, and is to nm in diameter (ohlinger et al., ; parra & prieto, ) . disease symptoms are characterized by high morbidity and mortality in rabbits over weeks of age. younger rabbits often survive infection and may develop antibodies to rcd virus (nagesha et al., ) . clinically, rcd symptoms are expressed after an incubation period of to h in which a febrile response and increasing lethargy are observed. infected rabbits typically die within to h postinfection and % mortality is observed after days. necropsies show a pale swollen friable liver, enlarged spleen, and clots in blood vessels. death is ascribed to acute necrotizing hepatitis and possible hemorrhaging (fuchs & weissenbrck, ; studdert, ) . however, necropsies close to the time of death show an absence of hemorrhaging and inclusion of hemorrhagic in the name of this rabbit disease that indicates the cause of death is misleading (studdert, ) . a different viral disease is responsible for european brown hare syndrome (ebhs) which causes severe hepatic necrosis in hares (lepus europaeus pallas and l. timidus linnaeus). the disease was first recorded in sweden in , and spread through continental europe and reached the united kingdom in (fuller et al., ) . in sweden, losses of hares to ebhs occurred years prior to sympatric rabbit populations developing rcd. similar observations were made in the united kingdom where hares began dying from ebhs years before rcd was observed in rabbit populations (fuller et al., ) . electron microscopy, nucleotide sequencing, and experimental cross-transmission studies have indicated that rcd virus and ebhs virus are closely related (le gall et al., ) but distinct members of the caliciviridae (chasey et al., ; nowotny et al., ) . disease symptoms are generally similar for rabbits and hares but show distinguishing characteristics in necrosis of liver lobules and clotting of blood vessels (fuchs & weissenbrck, ) . serological studies on rabbit sera collected in from czechoslovakia and austria indicate that rcd virus probably evolved from an apathogenic strain endemic to europe from at least this time (nowotny et al., ) . studdert ( ) speculates that the causative agent of rcd probably existed in europe as a quasi species, a collection of indifferent mutants with a variety of accumulated nucleotide changes. in this scenario, mutants occupied a specific ecological niche until one strain better adapted to prevailing conditions became the dominant member of the population. adaptation may have occurred because mutations caused increased virulence in an avirulent rabbit virus or increased the host range of hare-infecting viruses by allowing mutant strains to bind more efficiently to surface receptors on rabbit hepatocytes. given studdert's ( ) speculative scenario, rcd virus may be a highly evolvable organism. european rabbits appear to be the only animals susceptible to infection by rcd virus, and vaccines have been developed to protect domestic animals (boga et al., ) . other rabbits including cottontail rabbits (sylvilagus spp.), black-tailed jack rabbits (lepus californicus gray), volcano rabbits [romerolagus diazi (ferrari-prrez)] (gregg et al., ) , and hares (gould et al., ) are not affected. the limited host range of rcd virus makes it an obvious candidate for use in a biological control program against european rabbits in new zealand and australia. a joint biological control program between these two countries using rcd virus was initiated in and a strain of virus from the czechoslovakia republic was imported into australian quarantine facilities in to test effects on nontarget species (robinson & westbury, ) . host-specificity testing of nontarget species in australia for susceptibility to rcd virus further verified the limited host range of this natural enemy. test subjects in-cluded domestic lifestock (horses, cattle, sheep, deer, goats, pigs, cats, dogs, and fowls) , noxious exotic vertebrates (foxes, hares, ferrets, rats, and mice), native mammals (eight species), birds (five species), and reptiles (one species). there was no evidence for viral replication, clinical signs, or lessions in any organisms tested (gould et al., ) . artificial inoculation of rcd virus in north island brown kiwis (apteryx australis mantelli bartlett) and lesser short-tailed bats (mystacina tuberculata gray), both native to new zealand, also failed to produce disease symptoms (buddle et al. ) . the apparent host specificity of rcd virus to rabbits, rapidity of action, and the capacity to infect rabbits from other rabbits, [through feed and feces, or from a contaminated environment (o'brien, ) ] prompted further evaluation of this biological control agent under field quarantine conditions in australia. studies monitoring the effects of rcd virus on rabbit populations were initiated on wardang island near adelaide off the south coast of australia in (rudzki, ; robinson & westbury, ) . in september , rcd breached quarantine and appeared on mainland australia, possibly carried there by calliphorid flies and onshore winds (cooke, ; lawson, ) . attempts at containment failed (seife, ) . within months of the initial discovery of rcd virus on the mainland, an estimated million rabbits were killed in south australia. in dry areas, to % of infected populations died (anderson, ) with dead rabbits averaging per hectare. elsewhere, fatality rates were closer to % (anonymous, b) . in the period from october to november , an estimated total of million rabbits died from rcd in south australia and the majority of surviving rabbits were less than weeks of age (cooke, ) . the development of resistance in young rabbits may have profound effects on the long-term population dynamics on the rabbit-rcd virus system. ten arthropod vectors of rcd virus have been identified and include flies, mosquitoes, and rabbit fleas (anonymous, b) . rates of spread of rcd are greatest in spring and autumn at to km a day and are correlated with peaks of insect activity. dispersal of the disease probably has been assisted by humans moving contaminated material to new areas (cooke, ) . increased attacks on native fauna by exotic predators such as foxes because of declines in rabbit numbers do not appear to have occurred because predator populations have declined with rabbit numbers (anonymous, b). the virus is now endemic in australia and will probably be officially declared as a biological control agent under the biological control acts of the commonwealth and states (robinson & westbury, ) . rcd virus was smuggled into the south island of new zealand by high country farmers in august and illegally disseminated by feeding rabbits carrots and oats satu-rated with contaminated liquefied rabbit livers. a network of cooperators spread the virus over large areas of the south island and its subsequent spread (human assisted through the movement of carcasses, baiting, and insect vectors) made containment and eradication of the disease impossible. such actions by farmers clearly violated new zealand's biosecurity act, which was enacted in part to protect agriculture from unwanted introductions of pests. the new zealand government has sanctioned controlled virus releases into new areas. the short-term impact of rcd on new zealand rabbit populations has resulted in to % mortality in central otago and large-scale field studies are planned (g. norbury, personal communication, ) . cats on oceanic islands have been subjected to biological control with pathogens. six cats were introduced onto marion island in the indian ocean in (howell, ) ; by , numbers were in excess of and were increasing an average of % per year (van rensburg et al., ) . populations were sustained by consuming approximately , seabirds yearly and cats were probably responsible for the local extinction of the common diving petrel pelecanoides urinatrix (gmelin) (bloomer & bester, ) . surveys of cats on marion island revealed the presence of feline herpes virus and feline corona virus, but the highly contagious feline parvo virus was absent in the population (howell, ) . initiation of a biological control program with feline parvo virus, the causative agent of feline panleucopenia, began in with the release of artificially inoculated feral cats collected from the island (howell, ) . the disease reduced cat numbers by % after years by reducing fecundity and increasing mortality of juvenile cats (van rensburg et al., ) . virions found in high concentrations in feces, urine, saliva, and vomit were transmitted through direct contact between cats or contact with contaminated objects (howell, ) . annual declines of cat numbers were % from to . this rate decreased to % per year from to and was accompanied by lower titers of virus in serum samples collected from feral cats, indicating that viral efficacy was decreasing (van rensburg et al., ) . at reduced densities, hunting and trapping became viable and have been incorporated into an ongoing eradication program that may be assisted by the use of trained dogs (bloomer & bester, ) . sexually transmitted diseases have adverse effects on domestic and wild vertebrates by reducing survival, conception rates, and numbers of offspring born and successfully weaned (smith & dobson, ) . rabbits are susceptible to infections of venereal spirochetosis (treponema cuniculi), which causes sterility (smith & dobson, ) . goats can develop trichomoniasis, a sexually transmitted disease caused by the flagellated protozoan trichomonas foetus (reidmuller). this pathogen has been suggested as a bio-logical control agent for goat populations on oceanic islands that lack this microparasite (dobson, ) . sexual transmission of diseases may further guarantee host specificity in biological control programs. it also enhances the ability of parasites and pathogens to persist in low-density populations or solitary species (e.g., predators). the rate of spread of sexually transmitted organisms is tightly correlated with mean and variance of the numbers of sexual partners per host because of the need for host-tohost contact (horizontal transmission) for transmission. host population density is not important with respect to persistence or rate of spread of sexually transmitted diseases. this property, coupled with asymptomatic carrier states, long infectious periods, or vertical transmission (infective propagules are passed from mother to offspring), greatly enhances the ability of pathogens to persist in lowdensity host populations (smith & dobson, ) . because sexually transmitted organisms can persist in low-density populations or populations of declining density, the potential of genetically engineering sexually transmitted viruses to sterilize infected hosts is being investigated (barlow, ) . viruses that have antigens from the host sperm, or the zona pellucida around host eggs engineered into the genome provoke an immune system response that renders the recipient sterile. immunocontraception (also referred to as immunosterilization) as a means to control noxious vertebrates is being actively pursued by australia and new zealand (mccallum, ) . an alternative approach to immunocontraception is to use genetically modified microparasites to prevent lactation in females so that juveniles are not successfully weaned or to interfere with hormonal control of reproduction (cowan, ; jolly, ; rodger, ) . many species that become pests are distinguished from nonpestiferous species by their higher intrinsic rates of increase (rm). pest vertebrates have high rm values characterized by large litters, and by maturing sexually at young ages. agents that reduce reproductive rates may be more effective for control than mortality-inducing biological control agents are because resistance development should take longer to occur and population recovery would be slower (tyndale-biscoe, b) . resistance development may be further delayed by combined use of multiple agents that affect fertility in different ways [e.g., using agents that cause sterilization, alter levels of reproductive hormones, or affect lactation (cowan & tyndale-biscoe, ) ]. in sexually reproducing vertebrates, proteins associated with male and female gametes are potentially foreign antigens in the opposite sex. exposure to reproductive antigens occurs when females receive sperm and accessory fluids from males during copulation. as a general rule, females do not develop antibodies to these antigens because physiological and immunological mechanisms have evolved to prevent this (robinson & holland, ) . inoculation of sperm into females of the same species either subcutaneously or intramuscularly produces high sperm antigen antibody titers in recipients. in most cases, this causes either permanent or temporary infertility in females. such results indicate that sperm antigens in the reproductive tract are tolerated and that exposure to these antigens by different routes overcomes protective mechanisms, with infertility resulting (robinson & holland, ) . sperm antibodies in females that can arise from either systemic or local immune responses are found in cervical mucus, genital fluids (e.g., endometrial, tubal, and follicular fluids), and blood. antibodies bind to sperm, often in specific locations such as the head, midpiece, tail shaft, or tail tip. once bound to sperm, antibodies cause agglutination (e.g., irreversible binding to cervical mucus that normally aids sperm transport) or immobilization of sperm. antibodies may also interfere with acrosome reactions preventing ovum penetration and fertilization, or they block the binding of sperm to the zona pellucida (shulman, ) . the zona pellucida (zona) that surrounds growing oocytes and ovulated eggs is antigenic and available to circulating antibodies during oocyte growth and ovulation. nonreproductive tract inoculation of females with zona preparations leads to infertility (millar et al., ) . antibodies produced in response to administered zona antigens bind to the zona and prevent sperm penetration (millar et al., ) . zona glycoproteins are highly conserved among mammals, for example, nonspecific pig zona preparations cause infertility in humans, primates, dogs, rabbits, horses, and deer (robinson & holland, ) . a major objective in immunocontraception research is isolation of species-specific zona glycoproteins that do not cause sterility induced by immune response in species from which zona preparations were not derived. low variability among zona glycoproteins may limit the number of species-specific zona preparations for immunocontraception (millar et al., ) . immunocontraception for wildlife population control has been successfully implemented for horses (equus caballus linnaeus) (kirkpatrick et al., (kirkpatrick et al., , . free-ranging feral mares inoculated by dart gun with porcine zona pellucida showed depressed urinary estrogen concentrations and failure to ovulate. zona booster inoculations given years after initial inoculations prevented conception in treated horses for a third year compared with control populations that were not vaccinated. contraceptive effects were reversible after years of consecutive treatment, but prolonged treatment ( to years) with zona preparations caused irreversible ovarian dysfunction and fertility loss (kirkpatrick et al., (kirkpatrick et al., , . similar results have been achieved with porcine zona pellucida inoculations in whitetail deer [odocoileus virginianus (zimmerman)] (kirkpatrick et al., ) . gametic antigens that induce immune response can be administered by baits that are ingested by target organisms or can be inoculated directly into hosts with darts or bullets (tyndale-biscoe, b). injection of foxes with sperm antigens reduces fertility from to %. baits are considered the favorable method for delivering antigens to foxes in australia. potential baits include dried meats that contain microencapsulated antigens. use of recombinant bacterial vectors (e.g., salmonella typhimurium) also are being considered. an orally administered agent needs to reach the lower gastrointestinal tract to stimulate a response in the common mucosal immune system in the gut-associated lymphoid tissue. this in turn induces mucosal immunity in the reproductive tract of female foxes and causes sterilization (bradley et al., ) . at present, an effective bait specific to foxes that is environmentally stable and easy to manufacture has not been developed. nontarget impact is a concern because most antigens exhibit some specificity to the family level only. effective vaccines for rabies have been delivered as oral baits to foxes in europe, demonstrating the baiting technique is an effective dissemination method (bradley et al., ) . models indicate density-independent factors such as drought and rain (which affect pasture growth and rabbit numbers) strongly influence the effectiveness of baitdelivered fertility control in reducing fox abundance . an alternative proposal to deliver antigens orally is to develop transgenic plants to produce and deliver gametic antigens in palatable form to herbivorous pests. plants could be sown over target areas and allowed to become self-propagating vaccines. transgenic seeds, fruits, or leaves (e.g., transgenic carrots or maize) could be harvested and used as oral baits delivered to specific sites such as fenced watering points that allow pest animals access while excluding lifestock (smith et al., ) . baiting is an expensive form of control that requires monitoring of dosage and uptake rates and multiple areawide applications. problems of hormonal modification of behavior and delayed population control are additional drawbacks. one advantage is that baits can be used to treat localized populations that are problematic. similar shortcomings exist with antigen inoculations by projectiles where cost estimates are significant. to control the estimated , wild horses in australia with dart-delivered porcine zona pellucida would cost $ (australian) per horse per year compared with cents for permanent control with a bullet (tyndale-biscoe, ) . lethal methods of control provide immediate impact on pest populations and reduce pest status rapidly, with control being quickly observable. in contrast, fertility impairment is not immediate, population responses are delayed, and large proportions of populations need to be sterilized for this technique to be effective. large-scale distribution of gametic antigens might be possible through releases of host-specific microparasites expressing species-specific antigen genes (tyndale-biscoe, a , b . self-spreading and replicating parasitic vectors that have been genetically engineered and that may require periodic reinoculation into populations are analogous to augmentative biological control programs with traditional natural enemies (e.g., parasitoids, predators, or pathogens) released periodically for the control of pest arthropods. host-specific viruses carrying foreign dna could be cheap and effective biological control agents that have the potential to disseminate widely by sexual transmission, contagion, or arthropod vectors. the selected micro-or macroparasite must be able to carry foreign dna coding for gametic antigens, as well as promoters to express foreign genes and cytokines to enhance effectiveness (tyndale-biscoe, b). such agents must be able to reduce growth rates of infected populations and to maintain reproductive rates at lower levels (caughley et al., ) , and should not interfere with sexual behavior or social organization (caughley et al., ; robinson & holland, ; tyndale-bisoce, b) . with some pests such as rabbits and foxes, dominant members of populations make the main contribution to reproduction and inhibit breeding by subordinate members by occupying prime territories. ideally, a sterilizing agent should not change social hierarchies by allowing individuals with lower social status to successfully rear more offspring because this will cause pest populations to increase substantially (caughley et al., ) . genetically engineered agents should sterilize females because models predict greater population suppression with infertile females than with sterilized males (barlow, ; caughley et al., ) . in the absence of arthropod vectors, sexually transmitted diseases engineered to cause sterilization are superior to nonsexually transmitted ones because multiple matings with sterilized females increases contact rates and the competitive ability of the engineered agent with nonsterilizing strains. the impact of immunocontraception is further enhanced if the sterilizing agent causes limited host mortality and there is low naturally occurring immunity to sexually transmitted diseases (barlow, ) . sexually transmitted herpes-type viruses are being proposed as vectoring agents to induce sterilization in brushtail possums in new zealand (barlow, ; barlow, ) . the recently identified borna disease virus that causes wobbly possum disease in new zealand may be a suitable alternative to a herpes virus (atkinson, ) . the myxoma virus and murine cytomegalovirus are being investigated as gamete antigen delivery agents for rabbits and mice, respectively, in australia (mccallum, ; tyndale-bisoce, b; shellam, ) . four potential insertion sites for genes coding for gametic antigens have been identified in myxoma virus and recombinants have been constructed to express two esherichia coli (escherich) enzymes and influenza virus hemagglutinin genes. the ability of a novel myxoma virus to compete and spread among existing myxoma strains in field situations has been demonstrated by monitoring the spread of virus containing identifiable gene deletions (robinson et al., ) . the myxoma virus that can express foreign genes may operate as a vector for gametic proteins (robinson et al., ) . work is continuing on isolating and inserting rabbit gamete antigen genes into the myxoma virus genome (robinson et al., ) . the responses of experimental rabbit and fox populations in australia to imposed sterility by surgical ligation of fallopian tubes in females have been studied in an attempt to simulate the effects of virally mediated immunocontraception after recombinant virus establishment in wild populations. this technique prevents conception among predetermined proportions of females in populations without interfering with hormones or reproductive behavior (williams & twigg, ) . the dynamics of rabbit populations enclosed by rabbit-proof fencing that exhibited , , , or % sterilization of females were studied in each of two locations in western and eastern australia where climate patterns differed. females born into treatment populations were trapped and sterilized to maintain the same overall sterility levels (williams & twigg, ) . juvenile rabbits born into populations with sterilized females exhibited greater survivorship because of lowered competition for resources. this greater survival compensated for decreased fertility, but recruitment rates were ultimately constrained by environmental factors (e.g., depletion of vegetation). in populations with % sterility, reduced juvenile mortality did not compensate fully for lowered reproduction, smaller numbers of rabbits were recruited into these populations, and numbers subsequently declined. these results indicate that levels of sterilization with a genetically altered micorparasite have to reach at least % to achieve reductions in population density (williams & twigg, ) . surgical sterilization does not affect reproductive behavior in treated populations. sterile dominant female rabbits maintain hierarchical dominance, increased body weight over control females, continued to defend prime territory, and engaged in normal reproductive behavior including breeding burrow construction (tyndale-bisoce, b). birth rates of sexually mature females were in direct proportion to the level of fertility in experimental populations, indicating that fertile females did not respond to female infertility or decreased densities of young by producing larger litters (williams & twigg, ) . sterilized females tended to live longer than unsterilized females. this increased longevity suggests that sterile females may proportionately increase as treated populations reach an equilibrium density. obviously, larger proportions of sterile females reduce population productivity and the numbers of fertile females that a sterilizing microparasite would have to infect and sterilize. higher proportions of sterile females may reduce numbers of infective individuals harboring sterilizing microparasites and numbers of vectors (e.g., fleas that would spread an engineered myxoma virus), and may contribute to decline of transmission rates. these interactions need to be clarified and mathematical models may be of use here (williams & twigg, ) . engineered microparasites that sterilize pest animals offer the possibility of humane control without killing or causing animals to suffer the effects of debilitating disease. as a form of biological control, immunocontraception may also reduce the need for broadcast distribution of toxins for pest suppression, thereby reducing environmental contamination and nontarget mortality. this is of special concern when pests inhabit suburbs, urban parks, government and state campuses, nature reserves, military bases, or other areas where lethal controls may no longer be legal or safe (kirkpatrick et al., ; williams, ) . the concept of virally mediated immunocontraception has generated considerable debate on legal and ethical issues concerning releases of engineered microorgansims into the environment. once contagious recombinant agents that cause permanent sterilization in animals are released into the environment they cannot be recalled (tyndale-bisoce, ) . several potential risks are recognized. first, engineered viruses that are host specific and contain species-specific antigens could mutate and infect and sterilize nontarget species after release (anderson, ) . under such conditions it may be difficult if not impossible to contain and eradicate a mutant virus from an infected animal population that is abundant, secretive, and free ranging. second, sterilizing viruses either might cross international boundaries accidentally or be maliciously moved to sterilize desirable organisms in new areas (tyndale-bisoce, b) . for example, viruses engineered with little host specificity to sterilize widely dispersed marsupial pests in new zealand may enter australia and infect endangered wildlife (rodger, ; mccallum, ) ; engineered myxoma viruses may spread from australia into the americas and sterilize native rabbit species (tyndale-biscoe, ) . third, dart-delivered contraceptives used for wildlife control in the past have had adverse effects on individuals within target populations. changes in morphology of repro-ductive organs, secondary sexual characteristics, and behavior have been observed. viruses that induce sterility could alter genetic profiles of target populations because infectious agents may act as a new reproductive disease and individuals may exhibit differential susceptibility (nettles, ) . fourth, public concerns over the use of viruses and genetic engineering indicate substantial apprehension about the use of sterilizing viruses for pest management, these fears that need to be fully alleviated may delay or prevent field trials and widespread application (lovett, ) . despite potential drawbacks, immunocontraception is a potentially cost-effective method for reducing pest impact on endangered native species (sinclair, ) and on agricultural yields, and is an additional tool for sustainable pest management (williams, ) . a sterilizing agent that does not cause painful disease symptoms is an ethically acceptable form of pest control that is justifiable from animal rights perspectives, because it does not cause the suffering typical of current lethal methods (e.g., trapping, shooting, poisoning, and introduced disease) ( oogjes, ; singer, ) . under certain circumstances, the use of vectors to disseminate genetically engineered viruses is warranted (mccallum, ) . experience with the myxoma virus in australia indicates that it has not been deliberately or accidentally spread to any other country since its introduction in the s because of either the lack of suitable arthropod vectors or the inability of the virus to establish where different strains are already present. this history may indicate possible difficulty for unintentional establishment of genetically engineered microparasites in new areas, and establishment of engineered myxoma viruses may be possible only with carefully timed and repeated releases into rabbit populations (tyndale-biscoe, ) . however, such safeguards may be moot if a highly competitive sterilizing strain is engineered and released. quarantine legislation designed to prevent accidental or intentional but illegal importation of unwanted organisms would be exercised by countries under current international obligations and should impede establishment in new countries if rigorously enforced. however, current legal safeguards may be insufficient. new zealand's experience with rcd indicates it is possible for lay people to illegally import and establish reproducing populations of exotic pathogens. in australia, rcd breached a carefully planned quarantine on an offshore island. unintended establishment and proliferation of engineered viruses may be contained if outbreaks are recognized early, and if proportions of susceptible individuals are removed rapidly from the population either by culling or by immunizing against the pathogen (tyndale-b iscoe, ) . this has never been tried with wild animal populations. the containment of contagious pathogens, such as foot and mouth disease in livestock, indicates such an approach may be possible. highly attenuated forms of myxoma virus are used to protect wild and domestic rabbits in france and the united states, indicating the availability of such technology for this virus at least (fenner & ross, ; tyndale-biscoe, ) . limited field trails with sterilizing microorgansisms are unlikely before (anderson, ). there is abundant evidence that introduced exotic vertebrates that establish feral reproducing populations have disastrous consequences for agriculture and preservation programs for native plants and animals. sources of current vertebrate introductions include sellers and buyers of exotic pets; acclimatization societies that import, establish, and relocate game animals and whose constituents include hunters and fishermen; and farmers and ranchers who import and experiment with novel lifestock (e.g., fitch farming). exotic vertebrates have in some instances great economic importance (as with lifestock and game animals), they also enjoy public popularity because of interest in hunting, fishing, eating, or viewing large and unusual animals in familiar environments. the negative ecological aspects of introduced vertebrates may be poorly understood by the public at large. such limited understanding may hinder control efforts and prevention of importation (bland & temple, ) . legislation has been passed in the united states to minimize risks of importing new and relocating existing vertebrate species. the lacey act passed in and ammended in was enacted to protect certain animals and endangered habitats, and to prevent introduction of noxious pests. under the act, violation of the law can result in fines and imprisonment [see usc w importation or shipment of injurious mammals, birds, fish (including mollusks and crustacea), amphibia, and reptiles; permits, specimens for museums; regulations m for more details]. similar legislation has been developed in new zealand. the biosecurity ( ) and hazardous substances and new organisms (hsno) ( ) acts were devised to protect the environment by preventing or managing the adverse effects of hazardous substances and exotic organisms. campbell ( ) points out that existing laws have many loopholes and are not effective when applied, indicating a need to improve existing regulations and to develop new laws to curtail unwanted entry by alien vertebrates. one proposal is to require importers of exotic organisms to develop "clean lists" and to prove that organisms are not potentially invasive and disrupting to native ecosystems (campbell, ) . legislative approaches limiting imports and exports of organisms may encounter complaints under the general agreement of tariffs and trade (gatt) that stricter quarantine measures are an unacceptable imposition of one country's environmental standards on others (camp-bell, ) . there is an obvious need for greater cooperation among interest groups, scientists, and legislators to devise solutions to problems associated with continuing introductions of exotic species and to provide direction for future action. as an evolutionarily stable control strategy development of resistance (behavioral or physiological) to pesticides (e.g., rodenticides) by vertebrates, and the need for repeated or multiple simultaneous control strategies (e.g., poisoning combined with trapping and hunting) indicate that control of vertebrates is an ongoing endeavor that attempts to reduce agricultural damage and losses (greaves, ) or to protect wilderness areas (cowan, ; morgan et al., ; payton et al., ) from pest damage. biological control has several advantages over chemical and cultural control practices (van driesche & bellows, ) : ( ) it is relatively cheap and biological control programs are often quicker to implement than to develop and to register new pesticides; ( ) use of carefully screened natural enemies increases selectivity of attack toward target pests; ( ) natural enemies in many instances are self-perpetuating and self-distributing; and ( ) development of resistance to natural enemies is extremely rare. one documented case of pests developing resistance to natural enemies is the development of resistance to myxomatosis by rabbits and corresponding attenuation of highly virulent strains of the myxoma virus to strains of intermediate virulence (fenner & ross, ) . the myxoma virusrabbit system in australia and europe is dynamic with increasing rabbit resistance selecting for more virulent strains of virus. this suggests that for the short-term, at least, the system is coupled in an antagonistic coevolutionary arms race (dwyer et al., ) . flexible natural-enemy behavior patterns and physiology have the potential to weaken evolutionary responses that can cause pest resistance to introduced control agents (holt & hochberg, ; jervis, ) . in comparison, pesticides and cultural controls tend to target a fixed physiological or behavioral function or pattern, and the resulting selection regime is constant allowing pests either to increase tolerance to poisons or to learn and develop avoidance behaviors (e.g., bait and trap shyness). spatial heterogeneity of natural-enemy attack limits selection pressure on hosts by natural enemies, thus reducing the rate of resistance development by pests compared with uniformly applied selection pressures such as pesticides. pests that escape attack move into enemy-free areas and continue breeding; thus, the rate of coevolution is reduced by susceptible pests in transient refuges (jervis, ) . at the metapopulation level, natural enemies may be ineffective selection agents because of widespread extinction and establishment of pest subpopulations that maintain pest susceptibility. additionally, resistance development may involve costs leading to a corresponding decrease in fitness. for example, increased tolerance to attack may reduce the pest's reproductive capacity and ability to compete for resources, or may increase susceptibility to other mortality agents (holt & hochberg, ) . there are opportunities to enhance biological control programs against vertebrate pests that cause social, agricultural, and conservation problems. in many instances, biological control offers the best chances for long-term control, particularly in isolated areas with rugged terrain, in suburban areas with high-density human populations, or in places where pests are nocturnal or secretive. biological control will not totally alleviate vertebrate pest problems. it may, however, reduce the vigor of pest populations, thereby reducing damage, minimizing nuisance value, or allowing native species to compete more effectively for food and breeding sites. programs could be initiated to simply reassociate host-specific micro-and macroparasites with pest populations that have depauperate natural-enemy faunas (dobson & may, ) , and there is no shortage of targets as small founding populations of vertebrates continue to invade and proliferate in new habitats. genetically engineered natural enemies are additional tools to aid biological control efforts. research with agents that cause immunocontraception will likely diversify as advances in molecular biology continue, and routes alternative to sterilization may be taken. this area of vertebrate biological 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predator removal experiments predation models for primary and secondary prey species can foxes be controlled by reducing their fertility? successful treatment of capillaria hepatica infection in an acutely ill adult the snake that ate guam essentials of conservation biology a primer of conservation biology the effect of habitat on the helminth parasites of an island population of the polynesian rat (rattus exulans) testing the concept of virally vectored immunosterilization for the control of wild rabbit and fox populations in australia progress towards using a recombinant myxoma virus as a vector for fertility control in rabbits. reproduction, fertility and development the australian and new zealand calicivirus disease program the disappearance of guam's wildlife likely targets for immunocontraception in marsupials the establishment and spread of myxomatosis and its effect on rabbit populations escaped rabbit calicivirus highlights australia's chequered history of biological control a relationship between plagues of the house mouse mus musculus (rodentia: muridae) and prolonged periods of dry weather in south-eastern australia extinction of an island forest avifauna by an introduced snake regulation of mouse colony abundance by heligmosomoides polygyrus population dynamics in wild and laboratory rodents the role of parasites in regulating host abundance a harebrained scheme the potential of murine cytomegalovirus as a vital vector for immunocontraception. reproduction, fertility and reproduction immunological reactions and infertility can predators regulate small mammal populations? evidence from house mouse outbreaks in australia mammal populations: fluctuation, regulation, life history theory and their implications for conservation fertility control of mammal pests and the conservation of endangered marsupials effects of wild pig rooting in a deciduous forest the effects of capillaria hepatica (nematoda) on natality and survival to weaning in balb/c mice population dynamics of an outbreak of house mice (mus domesticus) in the mallee wheatlands of australia: hypothesis of plague formation the potential of capillaria hepatica to control mouse plagues the geographic distribution and host range of capillaria hepatica (bancroft) (nematoda) in australia an experimental field study to examine whether capillaria hepatica (nematoda) can limit house mouse populations in eastern australia a manipulative field experiment to examine the effect of capillaria hepatica (nematoda) on wild mouse populations in southern australia neither human nor natural: ethics and feral animals parasitic and infectious diseases, epidemiology and ecology sexually transmitted diseases in animals plant-derived immunocontraceptive vaccines food specificity in interspecies competition studies of the life cycle infectivity and clinical effects of capillaria hepatica (bancroft) (nematoda) in mice, mus musculus experimental embryonation and survival of eggs of capillaria hepatica (nematoda) under mouse burrow conditions in cereal growing soils the role of helminths in the biological control of mammals rabbit haemorrhagic disease virus: a calicivirus with differences fertility control in wildlife the crc for biological control of vertebrate pest populations: fertility control of wildlife for conservation virus-vectored immunocontraception of feral mammals vermin and viruses: risks and benefits of viral-vectored immunosterilization changing social views of the desired degree of host range specificity of natural enemies of arthropods effects of feline panleucopaenia on the population characteristics of feral cats on marion island correlates of introduction in exotic new zealand birds when biotas meet: understanding biotic interchange science biological invasions and ecosystem processes: towards an integration of population and ecosystem studies the extent of biological control of rats with barn owls, tyto alba javanica in malaysian oil palm plantations. the planter biological control of vertebrate pest effectiveness and cost-efficiency of control of the wild rabbit, oryctolagus cuniculus (l.), by combinations of poisoning, ripping, fumigation, and maintenance fumigation response of wild rabbit populations to imposed sterility development and use of virus-vectored immunocontraception the characters of successful invaders the varying success of invaders biological control of vertebrates--a review, and an assessment of prospects for malaysia observations of the lifecycle of capillaria hepatica (bancroft, ) with a description of the adult acknowledgments i thank vincent d'amico, iii of bean's art ink for preparing the states geological survey provided information on the brown tree snake. key: cord- -yxttl gh authors: siegel, frederic r. title: progressive adaptation: the key to sustaining a growing global population date: - - journal: countering st century social-environmental threats to growing global populations doi: . / - - - - _ sha: doc_id: cord_uid: yxttl gh adaptation is an evolving long-term process during which a population of life forms adjusts to changes in its habitat and surrounding environments. adaptation by the global community as a unit is vital to cope with the effects of increasing populations, global warming/climate change, the chemical, biological, and physical impacts on life-sustaining ecosystems, and competition for life sustaining and economically important natural resources. the latter include water, food, energy, metal ores, industrial minerals, and wood. within this framework, it is necessary to adapt as well to changes in local and regional physical conditions brought on by natural and anthropogenic hazards, by health threats of epidemic or pandemic reach, by social conditions such as conflicts driven by religious and ethnic fanaticism, and by tribalism and clan ties. the principal problems with growing populations do not involve space although population density is a problem unto itself for reasons discussed in previous chapters. the main problems are how to nourish people with food and water. the chronic malnutrition that about billion people suffered from in is likely to grow in number in some regions due to global warming/climate change because humans cannot adapt to less food if they are already at subsistence rations. for example, the population in sub-saharan africa is million people. the population is projected to increase to about . billion in , an increase of about %. within the same time frame, the united nations estimates that acreage under maize cultivation in the region will decline by % because of heat and drought brought on by climate change. the loss of arable land for food production can be countered in sub-saharan africa if marker assisted hybridization of maize or maize genetically modified to withstand heat and drought come onto the seed market together with modified seeds for other food staples and if african nations that do not now accept gmo seeds do so in the future. if not, nations favored for food production by climate change will have a moral obligation to provide food staples to people in nations with declining food production at accessible costs based on their economies. it is clear that what happens in sub-saharan africa and other regions with declining cultivation acreage or that will bear other effects of climate change (e.g., drought, shifting rain patterns) will affect the rest of the worldwide community politically, economically, and socially. the earth's problems that associate with global warming/climate change will be further discussed in the last section of this chapter. water is the staff of life. it keeps the body hydrated and is necessary to grow food crops, hydrate food animals, and grow feed grains. chemically or biologically polluted water does not serve these ends. if ingested, contaminated water can result in sickness as discussed in chap. . water stokes industry and manufacturing as well, thus keeping economies in many countries contributing to a population's wellbeing by providing employment, goods, and services. ideally, these businesses contribute their fair share to a tax base that supports social needs (e.g., education, healthcare, maintenance of infrastructure). factory owners adapt and plan against water shortages by having a water recycling system in place but may also slow or stop production until operational water conditions return. citizens with a reliable water supply can adapt to periods of water shortage by limiting use according to mandates by government officials but still have water for basic daily needs. however, persons in nations with a chronic per capita water shortage may not have this option to serve their daily needs unless water is imported or new water sources are found (see chap. ). if imported water is not an option to meet immediate essential needs, an alternative adaptation for people (and animals) is to try to reach a location where water would be available to them. with growing populations, per capita water availability is greatly diminished (table . ), water shortages become endemic, and people are at risk of existing at subsistence levels or dying. most at risk from the lack of a basic water ration are pregnant women, infants, young children, and old people. water wars are a future possibility as nations battle for their peoples' survival unless political differences are set aside and projects are supported to develop and share water sources. in a welcome effort, jordan, israel, and the palestinian authority signed a memorandum of understanding in the world bank, december , with specific aims: ( ) produce millions of cubic meters of drinking water for a water-deficient region; ( ) pipe million cubic meters of water annually * km ( mi) from the red sea to the dead sea; ( ) build a desalination plant at aqaba that would supply water to aqaba and eilat; ( ) the israeli water utility would supply - million cubic meters of drinking water to the palestinian authority for the west bank population at a reduced cost; and ( ) there would be an inflow of water to slow and in the future perhaps abate and reverse the shrinking of the dead sea. funding for the estimated $ million, year project will come from the world bank, donor nations, and philanthropic groups. as the global population increases and more people in developing and less developed nations have more disposable income, there will be a growing draw on natural resources other than water and food to service their industrial, agricultural, and manufacturing needs and wants. competition can force economic wars among national and multinational corporations for the resources necessary to provide goods and services and thus drive up prices for resources. industries and manufacturing units that cannot compete economically for natural resources will shut down, thus contributing to unemployment and downturns in economies because of falling domestic demand. to keep order in the increasingly interdependent world economy, accommodation for shared natural resources (or substitutes for them) at affordable prices is the adaptationnecessary. this can be mandated by the world trade organization backed by other practical-minded international groups. another adverse effect of growing populations that is a national resource that can be lost at the expense of some countries to the benefit of others is brain power. this brain power has been cultivated at excellent universities in developing countries, often times at little or no cost to students (e.g., in medicine, science, engineering, economics, the arts) who attend and graduate in increasing numbers. where there are too many well-educated professionals but lack of employment opportunities for them in their fields of expertise, educated people have the option of relocating to another country that can nurture and use the expertise. many adapt to the employment problem by taking up this option. this may mean moving from a developing country to a developed country or from a less developed country to a developing or developed country. ultimately, this loss of citizens with special skills can hurt a country. to counter this brain drain or reverse it, a country can adapt by investing in its future to create programs and conditions that keep talented professionals home, or if they have emigrated, entice them to return. china and india are examples of countries that have successfully taken this tact. when there are increases in a population because of immigration, problems can ensue between immigrants and a general population. adaptation to diversity and the multicultural experiences it brings to a community is often not a comfortable change. the antipathy of some in a host country is based on slowness of the immigrants to learn the language and inability of host country citizens to understand what immigrants are saying among themselves. this makes citizens feel uneasy. some view immigrants as a threat to their own or a family member's employment or advancement. race difference is a factor that some cannot readily adapt to as is ethnicity with its traditions and customs unfamiliar to the general public. religion can be divisive if adherents to its beliefs engage in acts of hatred detrimental to the host country fueled by fundamentalists and zealots who interpret religious writings as giving them license to commit crimes or absolving them of the crimes. sadly, many citizens paint an entire religious community with the taint of the relatively few evildoers. adaptation to diversity is essential for our earth's citizenry with joint efforts by all to resolve worldwide issues (e.g., global warming/climate change) so as to become the keys to providing a sound future for coming generations. there has to be a shared attack on global threats, no matter what the language, race, ethnicity, or religious beliefs are, no matter social or economic status, no matter whether a threat affects less developed, developing, or developed countries. adaptation is a progressive process when dealing with natural hazards because as each type of natural hazard impacts global communities over time, lessons are learned from each one that give direction to the methods of adjustment. adaptation to living where hazards can be expected to strike and where populations continue to increase is dependent on what we learn from the study of past hazards. we can use this evaluation of measured and observed data to minimize the immediate effects and aftermaths of hazards and protect citizens from injury, death, and from damage or destruction of property or infrastructure when hazards strike in the future. in areas prone to earthquakes, we know that earthquakes do not kill and injure people but that collapsing buildings and infrastructure do. earthquakes are not predictable so that there is no adaptation by a timely evacuation to minimize deaths and injury. however, building structures to make them more earthquake resistant can save lives, reduce injuries, and protect property. thus, after a high-magnitude earthquake, forensic engineering teams come to assess the damage and determine where and why damage and destruction took place within the context of the magnitude of an earthquake, the type of motion it originated (shaking, jarring, rolling), its duration, the area it affected, and the geologic properties of rocks underlying structures' foundations. hazard assessment teams also evaluate other factors that contributed to additional damage such as ruptured gas lines that feed fires and ruptured water lines that inhibit fire control. the engineers establish how construction can be improved in the future in terms of construction techniques and materials to prevent the types of collapses and utility failures they investigated. municipalities revise building codes accordingly to direct reconstruction and future building projects. where possible, structures that withstood an earthquake with minor or no visible damage should be retrofitted to improve their resistance to the next "big one." with each event, we gain more data on how to better construct earthquake-resistant structures and alter building codes to more stringent specifications. in theory, this adaptationto an irregularly recurring global event is good, but in practice it is most applicable to nations with the economic resources for reconstruction according to revised building codes and where there is no corruption to allow a bypass of the code. the same can be stated for retrofitting to give more resistance to earthquakes to existing structures. many developed nations and nations rich in commodity exports (e.g., oil) have a moral obligation to donate funds, material, and expertise to help citizens in economically disadvantaged nations recover from a destructive earthquake. some commodity-rich and economically sound nations do not do so directly, whereas others, big and small, rally to help disaster victims. for example, immediately after megatyphoon haiyan devastated many regions in the central philippines in , israel sent medical doctors and nurses and field hospitals to help philippine citizens recover from the impacts of the typhoon. as discussed in an earlier chapter, volcanoes are predictable in terms of becoming active by emitting wisps of smoke, bulging on a slope, warming of the soil or nearby pond or lake waters, emitting increasing concentrations of gases, and showing increased low-frequency seismicity. however, this activity does not always result in an eruption. a marked increase in measurements and observations, especially the low-frequency seismic activity, suggests that an eruption is imminent. adaptation to living and working on or near a volcano means investing in equipment to monitor volcanic activity and listening to alerts from scientists monitoring its activity and being ready to evacuate by gathering important papers and precious mementos and prepared to load into transportation for evacuation to safe locations. governments adapt by charging geologists to map out areas considered as high-, moderate-, and low-hazard zones in the volcano environs. geologists do this by studying rocks deposited from past eruptions and assessments of the topography. municipalities then pass zoning regulations applicable to the hazard level. governments have adapted to repeated periodic flooding in areas by creating flood control systems described in chap. . dams hold water during times of heavy and/ or extended rainfall and release any overflow into channels that move water away from urban or rural population centers. levees increase the volume of water that can move through a channel, thereby keeping it from spreading into populated areas and cultivated farmland. for smaller waterways that flow through cities, municipalities may invest in deepening, widening, and straightening channels as well as erecting walls so that more water can flow through the area more rapidly without coming out of a channel. governments define zones on flood plains according to a recurrence interval of damaging floods (e.g., years) as being off limits for residential and factory/plant construction. as much as we plan to adjust to living in an area prone to flooding, there is always the possibility of a megaevent that can overcome in situ control systems. therefore, as described chap. , governments adapt to this possibility by installing flood prediction equipment in drainage basins to provide warning to those at risk from rising and sometimes raging waters. the warning gives people time to gather important documents and personal treasures and evacuate to safe areas. the apparent increase in the frequency and magnitude of storms and resulting flooding in recent years is thought by many weather scientists to be related to global warming and the increased amount of moisture in the atmosphere from warmer oceans that gathers in clouds and precipitates during storms. this will be discussed further in this chapter. adaptation to extreme weather events such as an extended period of drought, heat waves, and frigid weather means preparation to wait them out. some municipalities adapt to repeated, sometimes seasonal, times of short-term drought by storing a - month water supply in surface or underground reservoirs during periods of normal precipitation that can be tapped (conservatively) as needed. others may plan to move water via pipes or water tankers from where it is plentiful to where drought conditions exist. otherwise, to survive, people move as best they can to where they have access to water. in instances of years long drought, crops and livestock and other life forms may be lost. heat waves can kill. adaptation to heat wave conditions means that water has to be available to people to avoid dehydration. where possible, homes should have air-conditioning or fans to keep people comfortable and municipalities should have cooling centers to which people can go. personnel should check on senior citizens and escort them to cooling centers if necessary. clearly, economically advantaged nations have the resources to give support to citizens during natural hazards such as these. these nations, international organizations, and ngos have a moral obligation to help economically disadvantaged nations as is possible when hazard conditions such as these threaten populations. the most extreme of weather conditions that can injure and kill people and destroy housing and infrastructure are tropical storms that evolve into violent hurricanes (typhoons, monsoons) by increasing wind speeds and sucking up moisture (water) as they track across oceans toward land. when these storms make landfall, they drive storm surges that can wreak havoc onshore communities, and as they move inland precipitate heavy rains that cause life-threatening and destructive flooding. these violent storms are destructive to coastal populations and island nations and have regional reach inland as they move along paths until they finally spend their energy or move out to sea. on november , , the typhoon named haiyan, the strongest recorded typhoon ever to make landfall smashed into the central philippines killing more than , people, injuring about , , and displacing almost , people. there was a -m (* ft) storm surge driven by winds measured at over km/h ( mi/h) with gusts reaching km/h ( mi/h). the typhoon flattened the city of tacloban that was home to , residents, and there was major flooding inland. the weather alerts led to a government call for evacuation away from the predicted path of the storm, and about million people followed the evacuation warning, surely saving many lives. access to aid typhoon-ravaged areas was difficult, and there were shortages of water, food, and medical care for many evacuees for several days. the philippine central government and local officials were not prepared to deal with a storm of this magnitude but help started arriving from many nations worldwide. there was a post-event concern of attending to sanitation needs of survivors to prevent outbreaks of diseases such as cholera, typhoid fever, hepatitis, and dysentery. if the philippine government had adapted by adopting better policies with respect to response to high-category typhoons in addition to the call for evacuation, the impact of haiyan would have been ameliorated. one would hope that this deficiency would be dealt with to limit the effects of future like disasters. evacuation to prevent injury and death in coastal zones that could be struck by high winds, heavy sustained rains, and storm surges is dependent on weather bureau forecasts and warnings from police, firefighters, or other government-authorized personnel. homeowners adapt to hurricanes by securing roofing with additional nails or special fasteners as a retrofit precaution and by boarding up windows on structures before an incoming storm hits. governments have adapted to the onslaught of violent high-energy storms by constructing seawalls of varying designs and heights to protect population centers by damping the force of storm surges. in china, for example, a seawall . m (* ft) in height and that has been heightened in the past protects shanghai from the full damaging effects of high-category typhoons. as a result of rising sea level, the shanghai seawall and other that protect coastal cities from being flooded by surges from high-energy tropical storms will have to be heightened to afford a greater degree of protection to people and property. wildfires can be a natural hazard when ignited by a lightening strike. however, most wildfires are started by human carelessness such as tossing a lit cigarette on a forest floor or failing to completely extinguish a campfire, or by arsonists. one may adapt to living in an area with a history of wildfires in two ways, neither of which is practical or promises % protection. first would be to clear an area of vegetation in a -m ( ft) swath around a dwelling or site for building. second would be to build with nonflammable materials so that embers propelled during a wildfire could not ignite a structure. adaptation to the advance of a wildfire would be to heed warnings to evacuate carrying a prepared case with important documents and other items of personal value. to delay evacuation by going back to retrieve something from then home can be fatal as it was for two people in a recent (june, ) wildfire that destroyed almost homes in colorado springs, colorado, usa. when there is a hazard event coming that calls for evacuation, responsible and often economically advantaged governments have adapted to the threat by designating evacuation routes, by providing transportation for people who need it, by having evacuation centers stocked with water and food, cots and blankets, basic medical supplies and medical personnel, and by having phone service available for people that need it. in the case of a primary or triggered hazard that happens with little or no warning (e.g., an earthquake, a tsunami, a volcanic mud flow), search and rescue teams should be ready to move in soon after dangerous conditions ease and they can move with safety. there should be medical attention to treat injured survivors, and stations set up as soon as possible to provide water, food, and other essentials available to those that survived with little or no physical hurt. these first steps at adaptation are the keys to survival. recovery after a shock phase can be long and drawn out, depending in grand part on a nation's social and economic resources and physical and economic assistance from other nations, international institutions, and ngos. change on our earth's inhabitants global warming is a fact attested to by an overwhelming majority of the scientific community and unwaveringly supported by a february joint publication of the us national academy of sciences and the royal academy in the uk on the causes and evidence for global warming [ ] . as noted in earlier chapters, during the past century, measurements show that the earth has warmed by * . °c (* . °f). global warming is an ongoing process that is attributed in grand part to a slow but continuous and increasing buildup of greenhouse gases in the atmosphere. the greenhouse gas most associated with global warming is carbon dioxide (co ). a plot of the increase of co content in the atmosphere with time against the increase in global temperature shows an excellent correlation of one with the other. additional lesser contributors include methane (ch ), nitrous oxide (no ), and chlorofluorocarbons (cfcs). with the beginning of the industrial revolution and the increased use of coal as the principal energy source, the content of co in the atmosphere was parts per million ( . %). the combustion of coal and later oil (petroleum) and natural gas emits co to the atmosphere. initially, and for many years thereafter, the added greenhouse gases were taken up by vegetation for photosynthesis and was also absorbed by the oceans and other water bodies. this kept the atmosphere co close to the ppm pre-industrial level. however, with increased industrialization, the need for electrical power, and the use of internal combustion engines, the amount of co generated was greater than what could be absorbed by nature and the content of co in the atmosphere increased. during june , its concentration reached more than ppm, an increase of over % over the pre-industrial concentration (scripps institute of oceanography mauna loa measurement). the increasing co content, other greenhouse gases, aerosols, and particles acted as a media that admitted sunlight (heat energy) to the earth's surface but did not let all of the heat escape back into the atmosphere. this abets global warming. in the past two to three decades, the rush to industrialization in developing countries (e.g., china, india, and brazil) and their growing power needs and vehicular use has thwarted the implementation of international agreements to reduce emissions from coal-fired power plants, other industrial and manufacturing operations, and the transportation sector. a direct consequence of global warming is sea level rise (slr) caused by the progressive melting of icecaps and ice sheets in greenland, the arctic, and antarctica, and of mountain glaciers in the himalayas, the alps, the rocky mountains, and the andes. the * -cm (* in) sea level rise during the past century may see a rise of another * cm (* in)- m (* in) during this twenty-first century. one-third of the rise would be from the expansion of warmer sea water, one-third from icecap and ice sheet melt, and one-third from mountain glacier melt [ ] . in , other researchers used computer models on existing data and proposed that % of sea level rise between and was from glacial melt [ ] . following the same line of investigation, other scientists studied satellite data and ground measurements from alaska, the canadian arctic, greenland, the southern andes, the himalayas, and other high mountains of asia and estimated that glacier contributions to sea level rise from to was % and together with ice sheet melt explained % of slr [ ] . a publication in estimated that ocean thermal expansion - m deep and - m deep contributed up to % to sea level rise [ ] . these latter two estimations are in line with the ipcc prediction for melting ice and ocean thermal expansion contribution to the estimated rise of sea level by the end of the century [ ] . with a rise in sea level, marine waters encroach on land. as the rise continues, possibly at an increasing rate, it threatens habitation in lowlying islands, coastal villages and farmland in lowlying zones, and heavily populated cities worldwide settled on inshore terrain close to sea level (e.g., bangkok, ho chi minh city, jakarta, manila, miami, new york, boston, buenos aires, london, rotterdam). rising sea level and warming of ocean waters have other ramifications that affect coastal communities as well as inland areas. as explained in chap. , the warmer surface water releases more water vapor with heat energy into the atmosphere. when the water vapor molecules condense in clouds, heat energy is released. this energy gives more force to tropical storms as they form, track to shore, and move inland, or storms that move close to and along a coast. these storms may transition to hurricanes (typhoons, monsoons) with the violent winds that cause destruction, and heavy rainfall that triggers flooding if they move onto land. we recognize that rising sea level means that tropical storms that impact a coast with storm surges have a farther reach inland with their destructive energy that is more pronounced when the surge occurs at high tide. the surges also saturate farmland they reach with salt water that harms crops. they also carry salt water into fresh water marshes and ponds, thus disrupting ecosystems there. the increase in the number of these extreme weather events and the increase in violence and destruction they wreak on land compared with like weather events in the recent past (e.g., during the past years) strongly suggest that they are fueled to a significant degree by global warming. there are two possibilities for adapting to the effects of rising sea level on coastal urban centers, one impractical, the other very costly but doable. the impractical adaptation possibility is to move at-risk population centers inland, out of the reach of the destructive tropical storms. this does not lessen the threat of flooding. the move is possible in some cases where land is available, but such a move is not economically feasible. one practical but costly adaptation to mitigate encroachment from sea level rise and the effects of tropical storm surges is to surround cities at risk within place seawalls - m higher than recorded high tides or higher depending on historical records and contemporary published data. the walls can have a concave configuration so that surging waves lose energy when their lower parts hit and are curled back on themselves damping some wave energy or there can be a different configuration best for the site(s) to be protected. similarly, gates buried at strategic locations where there is ship access to consider can be built to be hydraulically driven so that they can rise from a near shore seabed site to mitigate the effects of storm surges. both techniques have been used at different global locations. we have read that climate change affects land-based agricultural production, both for crops and animal husbandry. the warming climate at higher mid-hemispheric latitudes and at higher altitudes does not favor the growth and normal yield and/or quality of many crops. depending upon the degree of climate change and the linked change(s) that may follow it, farmers can adapt in several ways to maintain or increase crop yield and nutrition value. for example, when warming starts diminishing the productivity of a traditional crop, farmers can sow crops that are known to grow well in warmer temperature and give a satisfactory economic benefit. however, new groups of weeds, pests, and diseases will migrate to the warmer growth environment and will have to be dealt with in order to protect the new crops. where the effect of global warming reduces water supply for rain-fed agriculture, for crops irrigated with surface waters, and for groundwater-irrigated crops when aquifer recharge does not balances discharge, agriculturalists can adapt in two ways. first is the use of a more efficient irrigation method that delivers water directly to a growing plant (e.g., drip or focused irrigation). this minimizes runoff and loss to evaporation. second and similar to what was mentioned earlier is to sow a crop that needs less water to thrive and that delivers a good yield, good-quality product. another result of global warming for some farmlands is a longer growing season. in this situation, growers can adapt by planting earlier and have the possibility of double cropping. they can also grow a cultivar that is later maturing and that gives a product that brings a good market price. however, switching to new crops in a warmer growth environment means that there will be an invasion of a new set of weeds, pests, and diseases to ward off. in any efficient operation, and as emphasized in earlier chapters, farmers adjust to a changing growth environment for a given cultivar by applying the optimum amounts of fertilizer and other agricultural chemicals as might be needed that nurture and protect it most effectively. this reduces agricultural costs and lessens runoff of these chemicals to ecosystems where they can be harmful. global warming can bring on abnormal weather extremes that affect agricultural productivity. in these cases, farmers have to plan ahead based on recent history of these conditions in their regions. drought, heat waves, and long-term rain or heavy rain in a short time present problems for both cultivars and food animals. periods of less than average precipitation may last months or years. depending on the amount of the deficit precipitation, adaptation can include storing water in reservoirs and cisterns during times of rainfall to be tapped during a drought to sustain food animals and crops during a short-term, not too severe drought. there is also the option of trucking in water to sustain livestock. long-term droughts when precipitation deficits are high take their toll on plants and animals to the detriment of agriculture in a region especially when accompanied by heat waves. they have caused recent disasters for crops and food animals on all continents less antarctica. farmers either wait out the "bad times," change the type of cropping they do, the livestock they tend to, or change careers. the adaptation from crops that have been grown successfully before the effects of global warming reduced yields and quality of a harvest, to those "same" crops that can grow successfully under the advancing warming changes just described generally means that hybridized species have to be developed and used as warming increases at a location and slowly tracks to higher latitudes and higher altitudes. thus, growers turn to plants that are created by hybridization as described in chap. : traditional methods and marker-assisted selection methods within the same species, and genetically engineered (-modified, -manipulated) methods using different species. hybridization is a slow process, sped up markedly by genetic engineering, a method that yields foodstuff not accepted by the european union and many nations outside the union, especially in africa. bred species are developed to carry one or more characteristics that favor crop resilience against the effects of climate change. these include resistance to disease, weeds, and pests, and tolerant of drought (water stress), heat, short-term inundation, and short-term saline exposure (see chap. ). hybrids have also been developed to give higher yields and more nutritious crops. thus far, research has been focused mainly on improving seed for world staples such as rice, maize (corn), wheat, sorghum, and soybean. there have been great successes where hybrid crops were agriculturalists' adaptation so that the possibility exists that we can feed the earth's growing populations and reduce chronic malnutrition. when this is coupled with the opening of additional arable acreage and the use of improved farming methods for seeding, watering, and harvesting, global food security can be strengthened for the existing world population and the future generations on earth. however, this will require economic and technical input by developed nations and international groups. without basic sustenance, people will have less resistance to diseases and there may be local or regional population crashes if diseases evolve into epidemics or pandemics that invade susceptible populations. warming of the open ocean water, enclosed aquaculture operations in ocean waters and on land water bodies has affected marine fisheries and marine and estuarine aquaculture that grow food fish and shellfish, and lakes that sustain fisheries. in marine fisheries worldwide (e.g., in the north atlantic, off the coast of peru, off the coast of the philippines), some food fish or fish captured for other purposes (e.g., to use in pet food, to use to make fertilizer) have migrated to cooler water in ecosystems with conditions conducive to their spawning and growth. in some cases, predators follow fish they prey upon that have migrated to cooler waters, but in other cases they find new prey to sustain them. in other situations, they may become prey for larger fish in an ecosystem. fishing fleets adapt by following the fish they hunt into cooler waters where ideally they capture the hunted species in quantities allotted them by national and international fishery governing body regulations. if the quota system is followed, this will allow recovery of fish populations and sustainable harvesting. aquaculture operations that provide important supplies of food fish worldwide can adapt to warming waters by raising food fish or shellfish that will grow and multiply under the changed range of day/night temperature conditions if the fish they are farming cannot survive in the warmer waters. aquaculturalists also have the option to move their facilities to cooler-temperature waters, but the economic feasibility of doing this has to be evaluated by a benefit to cost analysis. this analysis has to be for the time frame during which the cooler-ecosystem waters are estimated to remain stable within the framework of a time range against global warming/climate change. another adaptation is that food fish currently being raised can be genetically engineered to be resistant to a warmer growth environment without changing their nutrition yield, growth rate, and ability to reproduce. there are diseases that are global threats, others that put regions at risk, and yet others that menace smaller political divisions. humans adapt to the threat of sickness in a population or a sickness itself in several ways. scientists develop methods to eradicate a virus or bacterium health threat, or a chemical/radioactivity threat. failing this, health professionals act to control a disease, to slow or minimize its transmission, and to apply approved therapies and support research to find therapies to treat an illness if one is transmitted. the following discussion draws strongly on the disease fact sheets put out by the world health organization. vaccines provide a main line of defense against many diseases. smallpox has been eradicated on earth by vaccination. polio has all but been eradicated globally except for a few pockets of the disease in pakistan, afghanistan, and nigeria where, in some cases, religious fundamentalists have beaten and killed health workers tasked with giving the vaccine to children, and in other cases where parents have been warned by the zealots against allowing their children to be vaccinated. recently, polio cases were diagnosed mainly in somalia but also in kenya. this is attributed to the fact that by , , children in somalia have not received the vaccine and are at risk from this highly contagious disease. it is also attributed to crossborder migration of infected persons into kenya. both governments are stepping up their vaccination programs. there were cases of polio diagnosed in the rest of the world in . measles is a global disease that can be prevented by a vaccine that is safe and cost-effective. measles may soon reach the near-eradication stage. in and subsequent years, . million people, mainly children under years of age, died from measles. since , billion children were vaccinated, million in . by , % of the world's children received the measles vaccine, up from % in . from to , deaths from measles dropped to %, from , to , . when the vaccination rate reaches %, mainly in low-income countries, the world will have brought another disease close to elimination [ ] . seasonal influenza is a global viral illness that afflicts - million people. the sickness kills , - , people with severe symptoms annually. transmission of the virus takes place when an infected individual coughs or sneezes without covering his/her mouth and releases droplets that can be inhaled by someone up to a meter away. transmission can also be from hands carrying the virus. seasonal influenza affects all age groups, but children less than years old, people over , and those with complicating medical problems are most at risk. influenza is a disease to be controlled. the principal control is by safe and effective vaccines that can prevent - % of influenza cases in healthy adults. secondary controls are obvious for infected persons: cover the mouth when sneezing or coughing, and wash the hands frequently. the influenza vaccine is taken once annually. because strains of the influenza virus change from year to year, adaptation is needed. the adaptation is via a vaccine that is prepared with or strains that scientists determine will be most common during a coming season [ ] . other types of influenza and respiratory illnesses have the potential to cause an epidemic or pandemic. they include avian flu and its strains and swine flu if the strains develop the ability for person-to-person transmission after infection, and sars (severe acute respiratory syndrome) and middle east respiratory syndrome (mers) because there is human-to-human transmission of the sicknesses. to the present, the outbreaks of the animal influenza diseases have been contained by quarantining infected people during treatment and by culling flocks and herds, or if available, vaccination of healthy animals. the latter two respiratory illnesses are caused by the coronavirus, and infected people have been in isolation wards. for sars, an illness that broke out in and spread to countries, isolation of victims and treatment with antiviral drugs and steroids stopped the disease during . mers is a recent ( / ) illness that has been confined to jordan, saudi arabia, qatar, and the united arab emirates. the mers virus has been found in camels. infected persons are quarantined in hospitals, but an effective drug treatment is still being sought to complement the normal hospital care-afforded patients. hiv/aids is a global epidemic that killed million people in three decades since . worldwide, in , there were million people with hiv, mainly ( million or %) in sub-saharan africa and south/southeast asia. the illness is caused by the exchange of body fluids (semen, vaginal excretions, blood, breast milk) from an infected individual with an uninfected person. more than % of the cases of hiv are from heterosexual activity. there is no vaccine against hiv/aids, no cure for it, but there is a cocktail of medicines (antiretroviral treatment) that control viral replication and allow an infected person's immune system to strengthen. this keeps the illness at bay and afflicted people in general good health and productive in their communities. in , only . million (less than %) of those with hiv in low and middle economies received the antiretroviral treatment. this is changing as more hiv carriers have access to antiretroviral therapy and there are more donations from economically advantaged countries to support hiv stabilization and reduction programs. the number of new cases of hiv is not exploding because more than % of those infected are following protocols that reduce the transmission of the disease. the prevention of transmission methods include access to male and female condoms, blood screening before transfusions, and needle and syringe exchange programs for sterile injections by drug users. hiv testing and education programs and hiv treatment help prevent transmission because individuals in continuous treatment have a very low probability of passing on the disease. male circumcision reduces the infection in men by about %. there is still much progress to be made because there were . million new cases of hiv in , with . million of that total in sub-saharan africa. the hiv/aids is a global sickness that is slowly coming under control because of generous donations from governments and foundations in developed countries added to what low-and middle-income countries themselves provide to lower the prevalence and incidence of hiv in their populations [ ] . tuberculosis (tb) infected . million people globally in , killing . million persons. it is a bacterial disease that spreads among people when infected individuals cough, sneeze, or spit, releasing bacteria into the air where they can be inhaled by others a meter away. although tb occurs worldwide, developing countries carry the largest burden of cases and deaths ( %). the bulk of new cases are regional in asia ( %) with sub-saharan africa reporting a large share as well with , new cases per million inhabitants. there is no vaccination for tb, but the disease can be treated and cured. the treatment is a half-year course of four antimicrobial drugs that must be taken without fail and thus requires continual supervision by healthcare personnel. more than million people have been treated and cured of tb since and perhaps million lives saved by following the who stop tb strategy protocols including securing adequate, sustained financing, ensuring early reliable detection and diagnosis, and providing approved treatment with a secure effective drug supply. the number of people infected with tb is declining, and from to , the tb death rate dropped more than %. the success in dealing with tb is muted somewhat because a strain of the bacterium that causes tb has evolved to be multidrug resistant (mdr-tb). in , , cases of this variant were reported (of the . million cases worldwide), mainly from india, china, and the russian federation. these are treated with, but do not always respond to, the most effective anti-tb drugs. research into new drugs to deal with this problem is ongoing [ ] . there is the question of whether people visiting or immigrating from these countries should be screened before a host country issues them entry visas. regional illnesses threaten the health of s of millions of people mainly in tropical and subtropical areas and often affecting children. one of these, the guinea worm disease, is trending toward elimination, if not eradication. this is a parasitic disease caused when people swallow water contaminated with infected water fleas (microscopic copepods) carrying worm larva. the worms release, penetrate the intestines, and move through the body migrating under the skin until they emerge causing swelling and blistering. people infected with guinea worm disease cannot contribute to their communities for months. during the mid- s, there were . million cases mainly in african nations. but attention to where the sources were so that they could be avoided and treated, and assistance in generating clean water, were adaptations that brought the number of cases down to less than , in . the number of cases continued to decline and was reduced to in in four african countries: south sudan, chad, ethiopia, and mali. there is no vaccine against guinea worm disease. health officials adapt to counter this sickness in several ways. as noted above, access to clean drinking water is the best way to prevent infection. the prevention or transmission of the worms from infected individuals to healthy persons by proper treatment and hygiene and the use of the larvacide temephos to eliminate the parasite-infected water flea vector and other prevention protocols are important in the control and effort to eliminate/eradicate the disease [ ]. the (jimmy) carter institute, atlanta, georgia, usa, has been a principle force since in the fight to rid the world of guinea worm disease. in tropical and subtropical regions, there are three mosquito-vectored diseases that put millions of people at risk: yellow fever, malaria, and dengue fever. yellow fever is an endemic viral disease in tropical regions of africa and latin america with , cases reported annually that cause , deaths. there is no set treatment for afflicted people, but there is an adaptive preventive measure. a vaccine against yellow fever is available that is safe, affordable, and that gives lifelong immunity to the disease with one dose after - days for % of the people vaccinated. when there is the onset of a yellow fever outbreak where the population lacks vaccination protection, mosquito control is an essential first step in adaptation to prevent or slowdown transmission of the yellow fever virus. spraying insecticides to eliminate breeding sites and kill adult mosquitos is the control used during epidemics to make time for vaccination campaigns in a population and for immunity to take hold. there are limitations to the application of the yellow fever vaccine. first is that babies less than months of age should not be vaccinated or, during an epidemic babies less than - months of age should not receive the vaccine. second, pregnant women should not be vaccinated except when there is an outbreak of the disease. third, people with a strong allergy to egg protein or those with a marked immunodeficiency or with a thymus problem should not receive the vaccine [ ] . malaria is a parasitic disease caused by the bite of an infected mosquito. there is no vaccine against malaria, but one is undergoing a clinical trial in seven african nations with results expected in . a use or no use decision as a control method for malaria will be made in . promising results from an early-stage clinical trial of an unconventional vaccine prepared with live, weakened sporozoites of the malaria parasite were published in . plasmodium falciparum was given to healthy - year-old volunteers intravenously. the volunteers were grouped to receive - doses and subsequently exposed to bite by five mosquitoes carrying the parasite. none of the six that received five doses were infected with malaria. three of the that received four doses became infected, whereas of the that received lower doses became infected. of that received no vaccine, became infected. those that became infected were treated with malarial drugs and cured. clearly, higher dosages give protection against infection by malaria [ ] . more research and extensive clinical trials are necessary to determine how children respond to the vaccine with adjusted dosages and whether the results from earlystage trial are reproducible in larger volunteer populations. if the results of additional clinical trials go well, the hurdle of producing enough vaccine and adapting it to injection has to be faced. forty percent of the deaths from malaria are of african children in the democratic republic of congo and nigeria. in addition to sub-saharan africa, populations in asia (especially india and the greater mekong region) and latin america suffer from the disease. the effort to deal with the disease that is preventable and curable now centers on control and treatment to reduce the number of cases. in , the who reported that there were million cases and , deaths (with an uncertainty range of , - , ). in a report, researchers suggested that the number of deaths was understated and that their computer model gave a figure for almost double, , , deaths ( % uncertainty interval of , - , , ) [ ] . the who stood by its figure stating that much of the data in the cited study were based on verbal testimony of how people had died, not on laboratory diagnosis of samples. either figure represents too many deaths from the disease and have to be reduced. mosquito control is the adaptation that can reduce the transmission of the disease greatly. this includes personal protection by use of proper clothing and/or the application of mosquito repellent, the use of longlasting insecticidal (pyrethroids treated) nets to kill mosquitos and prevent nighttime bites, and indoor residual spraying (remains effective for months). those people infected can be treated with oral artemisinin monotherapy followed by a second drug. failure to complete the treatment as prescribed leaves parasites in a person's blood. no other antimalarial treatment is available so that parasite resistance could become a serious problem. for visitors to a malaria region, antimalarial drugs taken before, during, and after a trip can protect them from the disease. many countries in tropical and subtropical areas have used the above-cited strategies and others to work toward the elimination of malaria. malaria eradication is the goal of the who [ ] . dengue fever is a female mosquito-borne virus that infects people with an influenza-like disease in tropical and subtropical regions worldwide. the disease can kill if it evolves to severe dengue. it is endemic in latin america and asia where most cases now occur. since the s, the sickness has spread to more than countries putting about % of the world's population ( . billion people) at risk. dengue fever is especially endemic to urban/semi-urban environments. humans are the main carrier of the virus. after a mosquito bites an infected person, each subsequent bite by the infected mosquito creates another carrier. a mosquito can bite many people each time it feeds. in the americas alone, there were . billion cases of dengue fever reported in with , being severe dengue. there is no vaccination against dengue fever, but research continues to develop one. the main treatment for afflicted persons is to keep them hydrated. adaptation to deal with slowing or stopping the spread of dengue fever involves three main tracks in addition to spraying insecticide to kill mosquitos. the best control method to prevent the transmission of the virus is to deprive mosquitos of sites with shallow, standing water where they can lay eggs and multiply. control can be improved if communities cover and clean water storage containers regularly, and use proven insecticides on them as necessary. finally, individual protection such as the use of mosquito repellants and insecticide-impregnated bed nets can help reduce the incidence of dengue fever as it has with malaria [ ] . although controls are known, they are not always applied because of economics and other factors that prevent access to protection methods. the result is that the number of cases of dengue fever reported continues to grow globally. as populations increase in urban locations, the incidence of dengue fever can be expected to increase as well unless strict controls are enforced until a safe and cost-effective vaccine is developed. a positive aspect of the dengue fever problem is that recovery from one serotype of the virus gives immunity for life. however, there are four serotypes of the infectious virus so that recovery from one leaves a person susceptible to the others [ ] . chagas is another regional disease. it infects - million people annually, mostly in latin american countries. it is a parasitic illness that evolves after the bite of a blood-feeding triatomine bug, often on the face, where it defecates close by leaving parasite-bearing feces. parasites access the body when the feces are inadvertently smeared into the bite, the eyes, the mouth, or any skin lesion. the parasites circulate in the blood expressing their presence as a purplish swelling of one eyelid or as a skin lesion. there are several other symptoms as well in this acute stage of the illness, but these may be absent or mild. if diagnosed early during this stage, chagas disease is treatable. the parasite is killed with the medicines benznodazole and nifurtimox taken for months. there are limitations as to who can take these medicines (e.g., not by pregnant women or people with kidney or liver problems). the untreated sickness can cause cardiac alterations and digestive problems that show up - years after an untreated infection. chagas disease can be spread by blood transfusion and by organ transplant, making blood screening for the parasite essential before a procedure. it can also pass to a fetus from an infected woman. there is no vaccination against the illness so that control of the vector (triatomine sp.) is necessary. the controls adapted by many municipalities include insecticide spraying inside a home, the use of treated bed nets, and hygiene practices that protect food, its preparation, and its storage before eating it [ ] . the sickness may recur if control practices become lax. chagas disease is spreading as populations emigrate from latin america to northern countries. blood screening of visitors or immigrants from the countries where chagas is endemic may be necessary, and treatment followed by an infected individual before a host country issues an entrance visa. this would prevent the ingress and possible spread of chagas. outbreaks of diseases in town and cities is most often caused by bacterium-contaminated water or food and poor sanitation. sicknesses such as cholera, typhoid, and various other diarrhea types are examples of such diseases. they are all highly infectious if good hygiene practices are not followed. these diseases are endemic in many countries where populations do not have access to safe water and adequate sanitation. there are vaccinations for some of these sicknesses that may require more than one dose, but they may not be completely effective or long lasting and require revaccination at times specified by medical personnel (e.g., after - years). otherwise, infected persons can be treated with medicines such as oral rehydration pills or antibiotics. adaptation for prevention is easier called for than realistically available: washing hands with soap and clean water after visiting the toilet, and as noted above, access to safe water and good sanitation. given the millions of people infected by these bacterial diseases and the hundreds of thousand that die from them annually, generally in economically disadvantages countries, there should be an expanding global priority to eliminate the disease-causing conditions, and preparedness to combat an outbreak when it is reported. there are important factors to consider when adopting plans to halt or meliorate the effects of health threats to people in the near and extended future. one is the climate change-driven spread of tropical and subtropical diseases discussed earlier to newly warmer and moister higher-latitude and higher-altitude zones. another is the growth of populations mainly in tropical and subtropical regions in africa, asia, and latin america. together with this latter factor are the increasing populations and population densities in urban centers especially in the regions just cited. an additional factor to consider is whether there is accessibility to populations by healthcare workers or by people to healthcare clinics or hospitals, well-staffed and well-stocked with necessary pharmaceuticals. certainly, future planning has to include funding to support research to develop vaccines for diseases that do not have vaccination as an option against an illness (e. g., malaria, dengue fever) . in addition, improvement of vaccines that are available but that are not completely effective in terms of protection or the length of time they are effective should be a priority in pharmaceutical and biotechnology laboratories. scientists presented a fine review of the status of vaccine research from the design and development of vaccines to discussion of vaccines and infectious diseases (e.g., hiv, malaria, tuberculosis, pneumococcal disease, and influenza) [ ] . they also discuss vaccines against enteric infections and viral diseases of livestock as well as vaccines against non-infectious diseases (e.g., cancer) and against chronic noninfectious diseases. continued and repeated education classes on how to prevent the transmission of diseases and free supplies of materials that work to this end (e.g., insecticide-treated bed netting, male and female condoms) are essential to reducing the prevalence and incidence of diseases as are safe water and uncontaminated food. as new medicines or combinations of medicines are developed, tested, and found to be effective in controlling diseases, they become part of the protocol for either curing disease or controlling disease to reduce transmission while allowing persons to carry on with their lives. in these times of easy and rapid migration, one wonders whether screening of visitors or immigrants for diseases known to be endemic or active in the countries or regions from which they come should be required so as to prevent a carrier from infecting others and spreading a disease (e.g., chagas disease, cholera, tuberculosis). this was done at airports during the sars scare for people leaving or entering a country (e.g., china) and likely limited the transmission of the sars virus and spread of the disease. preparedness for a disease outbreak, response to an outbreak, and management of resources during and post-outbreak are the keys to adapting to health threats that could affect future generations. this means developing the capability to extend the reach of health services to regions where climate change brings warmer, moister conditions to higher-latitude and higher-altitude ecosystems that are now reached by disease vectors that have expanded into these formerly cooler and drier environments as a result of global warming. adapting to this reality and planning ahead makes it possible to deal with and stem an incipient outbreak of disease before it is transmitted and spread to the general population. this becomes essential when there is a future disease outbreak in large, dense populations in tropical and subtropical urban centers as well as those in regions warmed and humidified by climate change to subtropical and tropical settings. remember that urban populations worldwide, especially in africa, asia, and latin america, are where much of the global population growth will take place during the next few generations. under these conditions, diseases can spread rapidly in many ways. these include from bites of vectors, by respired droplets after an infected person coughs or sneezes, and by touching surfaces bearing viruses, bacteria, or parasites. diseases are also spread by ingestion of contaminated water and/or tainted food, and by other methods of infection transmission. disease transmission can be checked by rapid response teams with appropriate and sufficient supplies to treat (and perhaps places to quarantine) those in the infected population. lastly, it must be noted that there are many other diseases in addition to those cited previously for which prevention, treatment, and cures are research priorities in laboratories worldwide. in addition, there are addiction diseases that can trigger health problems in important segments of society. these include smoking (e.g., emphysema, lung cancer), alcoholism (e.g., cirrhosis of the liver), drugs (e.g., various psychological and physical ills), and overeating (obesity, diabetes, high blood pressure). adaptation to these health threats involves public education forums through various media outlets, counseling, and sponsored groups with their individual group meeting, and programs are assisting many in breaking from an addiction to the benefit of a healthier life. adaptation to meet the health challenges in the past, and in contemporary times has been a slow, progressive adventure with many successes but with much yet to be done. this is the planned path for the future: meet the challenges of societal health threats, resolve many, and keep researching to resolve others. a special ipcc report in examines in a general way adaptation to a changing climate as a risk management approach [ ] . it uses pre-planning to reduce exposure and vulnerability to extreme hazard events by preparing for them beforehand, responding to their impacts on people, structures, and infrastructure, and having in place recovery systems that can act when a danger condition eases. in this way, there will be an ability of populations to cope with future risks brought on by a changing force with which a hazard impacts a community, changes in the frequency of an occurrence, and extension of the spatial reach of its destructive power. much of this has been discussed in the chapters of the book you are reading. an understanding of what is being done now to adapt to the various problems society faces during the second decade of the twenty-first stimulates proposals of how to adapt to them as global conditions change in the future. to this end, the world bank commissioned a study on the effects global warming as it increased from . °c that exists on our planet now to what can be expected if the warming reached °c, a change that many scientists believe we can adapt to, and then reached °c as warming continues [ ] . the study centered on regions with high population growth and great susceptibility to be negatively impacted by climate changes: ( ) sub-saharan africa where food production is at risk: ( ) southeast asia where coastal zones and productivity are at risk; and ( ) south asia where there could be extremes of water scarcity and excess. the effects of higher temperatures from global warming and climate change included what has been discussed in previous chapters of this book: heat, drought, sea level rise, coastal zones, typhoons, flooding, river runoff, water availability, ecosystem shifts, crop yields, fishing, aquaculture, livestock, health and poverty, and tourism. projections such as those published in the world bank study give impetus to governments, international institutions, multinational companies, private foundations, and ngos to think now, to invest now, and to research now for adaptations that can be realized in good time and that will provide global citizenry with a good quality of life where needed. in this book, we have examined existing human populations and the problems they are experiencing in the second decade of the twenty-first century and have also considered growing populations globally and additional problems future generations will experience. we have discussed strategies on how to cope with manyfaceted threats to citizens. these include how to nourish those who need food and water, how to shelter people safely from natural and anthropogenic hazards, how to provide them with healthcare, education, and employment, and how to prepare them for the evolving global warming and the physical and biological dangers that ensue from climate change. given the present global conditions with about % of our earth's population suffering from malnutrition and more than % not having access to safe water, our capability of nourishing a billion and a half more people by is in question. also problematical is our capability to provide for an additional billion people years later, or a total of at least . billion people by the turn of the century, that is, if we reach those population figures or have population crashes such as from pandemics that can kill scores of millions if a disease is not immediately treatable, or an unlikely but possible nuclear conflagration that could do the same. less likely yet is an explosion of a small asteroid or comet in the atmosphere such as happened in a poorly inhabited area of siberia in . here, an exploding mass more than m in size knocked down millions of trees in an area greater than , km (close to mi ) with energy thought to be , times greater than the hiroshima atomic bomb. clearly, such an event could kill the population of a megacity if it were to occur. another question is whether national governments are economically strong enough and have the will to set priorities that adopt strategies to protect citizens from natural (e.g., earthquakes) and anthropogenic (e.g., pollution) hazards as well as from extreme weather conditions that are supported by global warming (pollution of the atmosphere) but are naturally occurring. countries can also improve social and economic conditions by investing in health care and education for their citizens in order to form a sound and knowledgeable cadre that would be attractive to investors interested in locating a development project that would provide employment. again, this is in question given limited national economic capabilities and the increasing numbers of people to be accommodated, especially in several developing and less developed countries in africa, asia, latin america, and the middle east. at this point, we must ask, "what is the carrying capacity of the earth?" have we reached it at billion given the billions who are today under served in developing and less developed countries? some scientists will answer yes, whereas others believe that advances in agriculture and technology can allow population expansion although to what point is not defined. can countries that are poisoning their environments do a turn around to save their citizens from grief? can they exert controls on operations that create unhealthy conditions that sicken people, lessen agricultural production, and otherwise disrupt local, regional, and global climate change: evidence and causes ( p) intergovernmental panel on climate change ( ) climate change (as four part report). part . the physical science basis mitigation of climate change past and future sea level change from the surface mass balance of glaciers a reconciled estimate of glacier contributions to sea level rise ocean thermal expansion and its contribution to sea level rise tuberculosis. fact sheet no. p . world health organization ( ) dracuncukiasis (guinea-worm disease) protection against malaria by intravenous immunization with a non-replicating sporozoite vaccine global mortality between and : a systematic analysis world health organization ( ) malaria. fact sheet no. p . world health organization ( ) dengue and severe dengue chagas disease (american trypanosomiasis). fact sheet no vaccines and global health ) ipcc special report summary for policy makers. managing the risks of extreme events and disasters to advance climate change adaptation turn down the heat: climate extremes regional impacts and the case for resilience. a report for the world bank prepared by potsdam institute for climate impact research and climate analytics key: cord- -fkddo n authors: griffin, brenda title: population wellness: keeping cats physically and behaviorally healthy date: - - journal: the cat doi: . /b - - - - . - sha: doc_id: cord_uid: fkddo n nan o u t l i n e whereas feline practitioners are usually well versed in the creation of wellness programs tailored to individual cats, optimizing the health of a population of cats requires additional knowledge and poses unique challenges. these challenges will vary depending on many factors, including the nature and purpose of the population itself. indeed, veterinarians may be tasked with developing health care programs for cat populations in a wide spectrum of settings-from facilities housing laboratory animals, to animal shelters, home-based rescue and foster providers, care-for-life cat sanctuaries, breeding catteries, or large multicat households. regardless of the setting, a systematic approach to the health of the clowder is crucial for success. merriam-webster's dictionary defines wellness as "the quality or state of being in good health especially as an actively sought goal." ensuring population health requires careful planning and active implementation of comprehensive wellness protocols that address both animal health and environmental conditions ( figure - ). addressing physical health alone is not sufficient to ensure wellness. for example, a cat may be in proper physical condition and free from infectious or other physical disease, yet suffering from severe stress and anxiety. in this case, the patient cannot be assessed as healthy, because its behavioral (emotional) state is compromising its health and well-being. thus physical health and behavioral health are both essential components of wellness, and preventive health care must actively address each of these. addressing the environment of the population is also critically important when considering wellness. even the best-designed facilities cannot favor good health in a multicat environment without thoughtful implementation of environmental wellness protocols. in small animal practice, environmental wellness is frequently not emphasized simply because many owners are accustomed to providing a reasonably healthy environment for their pets. in contrast, a structured program to address environmental wellness is essential in the more specific goals will vary depending upon the given population and its purpose. for example, in an animal shelter, specific goals of the wellness program might include decreasing the incidence and prevalence of infectious diseases in the shelter and following adoption, decreasing the incidence of problem behaviors in the shelter, decreasing the rate of return of cats to the shelter for problem behaviors, increasing the adoption rate, and so forth. in the context of a breeding colony, the goals might include increasing kitten birth weights, decreasing neonatal mortality, or improving socialization of kittens. by identifying and tracking measurable factors (often called performance targets in large animal medicine), it is possible to measure progress toward these goals. once baseline data (such as disease rates) are established, it is possible to measure the impact of protocol changes on population health by evaluating these performance targets. both medical records and a system for regular surveillance and reporting are required to accurately track and access trends in animal health. early recognition is crucial for effective control of infectious disease and problem behavior in a group. therefore a regular system of health surveillance must be in place to monitor every individual. in a population setting, daily "walk-through rounds" represent the foundation of an effective animal health care program. rounds should be conducted at least once daily (preferably twice a day or more often, depending upon the needs of individual cats) for the purpose of monitoring and evaluating both physical and behavioral health. medically trained caregivers should visually observe every animal and its environment, taking note of food and water consumption, urination, defecation, attitude, behavior, ambulation, and signs of illness, pain or other problems. monitoring should take place before cleaning so that food intake and the condition of the enclosure, including the presence of feces, urine, or vomit can be noted. alternatively, observation logs can be completed by caregivers at the time of cleaning and reviewed during walk-though rounds. any cat that is observed to be experiencing a problem, whether it be signs of respiratory infection, diarrhea, anxiety, or obvious pain, suffering, or distress must be assessed and treated in a timely manner. regardless of length of stay, regular daily assessment is imperative to identify new problems (medical or behavioral) that may develop so that they can be identified and addressed in a timely fashion to ensure the welfare of the individual animal as well as that of the population. context of a population, regardless of the actual physical facility. proactive measures to maintain clean, sanitary environments that are not overcrowded-where cats are segregated by age and health status and provided with regular daily schedules of care by well-trained dedicated caregivers-are essential. simply stated, the overarching goals of a population wellness program are to optimize both the physical and behavioral health of the cats as well as preventing transmission of zoonotic diseases. in other words, a population wellness program should be designed to keep animals "healthy and happy" while keeping human caregivers safe. it is not difficult to identify a healthy population of cats: when wellness protocols are successful, cats "look healthy" and "act like normal cats." in other words, they appear in good physical condition and display a wide variety of normal feline behaviors, including eating, stretching, grooming, scratching, playing, rubbing, resting, and if allowed, courtship and breeding. just as changes in a cat's physical appearance should alert the clinician to potential problems, so should the absence of such normal feline activities and behaviors by members of the group. wellness goals must include maintaining the health of individual animals as well as that of the population as a whole. in the context of the population, the individuals that are physically or behaviorally ill serve as indicators or "barometers" of the health care and conditions of the population. when individuals are ill, their health and well-being is always a priority; however, it should also immediately trigger the clinician to ask, "why is this individual sick? what is the cause of its illness, and how can i prevent this from affecting others?" to optimize feline health, wellness programs must be carefully structured to address both the physical and behavioral health of the animals, which are intimately linked to their environment, making it crucial to systematically address environmental conditions as well. behavioral health . freedom from thirst, hunger, and malnutrition by providing ready access to fresh water and a diet that maintains full health and vigor . freedom from discomfort by providing a suitable environment, including shelter and a comfortable resting area . freedom from pain, injury, and disease by prevention or rapid diagnosis and treatment . freedom to express normal behavior by providing sufficient space, proper facilities, and company of the animals' own kind . freedom from fear and distress by ensuring conditions that avoid mental suffering in addition to early recognition of health problems, timely action is crucial to effectively limit their morbidity. ideally, all facilities that house multiple cats should have written policies and protocols in place that detail how medical and behavioral problems will be handled. , , a committee or team of individuals composed of medical staff, managers, and caregivers can establish and oversee these policies and protocols. such protocols serve as guidelines for systematic triage and care of animals and help to prevent delays in care that may otherwise arise if such plans were not in place. policies and protocols should be based on medical facts, taking into account the entity's purpose or mission and the availability of resources for care. they should include a definition or description of the disease or condition in question, a description of the methods that will be used for diagnosis, and a general policy regarding the handling and disposition of affected cats. in addition, protocols should include details on notification, housing, decontamination, treatment, and documentation (box - ). just as quality-of-life assessment is the responsibility of every veterinarian as they guide the medical care of individual animals, quality-of-life assessment is also a critical part of population health care and monitoring. the factors that affect physical and mental well-being are broad, complex, and often vary substantially among individuals. exacting criteria are lacking for the objective measurement of quality of life of cats. however, subjective assessments can and should be made by medical and behavioral personnel at regular intervals (weekly or even daily, as indicated) considering the most information possible. , the "five freedoms," which were originally described by the farm animal welfare council in the s, represent a benchmark for ensuring quality of life or animal welfare (box - ). these principles provide a useful framework that is applicable across varying situations and species and have been widely accepted and endorsed by animal care experts. many agencies have used the five freedoms as the basis of recommendations for minimum standards of care for many species, including cats housed in catteries, shelters, and research facilities. , , , the tenets of the five freedoms define essential outcomes and imply criteria for assessment but do not prescribe the methods by which to achieve those outcomes. regardless of the setting, population wellness programs should ensure the five freedoms for all cats. wellness always starts with prevention: it is far more time and cost efficient than treatment, and it is kinder to the animals and their caregivers. with this in mind, population wellness programs should provide broad-based, holistic approaches to preventive care, rather than being based on the control of a single disease or problem, regardless of the setting. maintenance of good health or wellness is especially challenging in populations with high turnover and interchange of cats of varying ages and susceptibilities, such as animal shelters. infectious diseases can become endemic in facilities where populations of animals are housed. even in closed populations, certain pathogens can be difficult to exclude or to eliminate once introduced. notably, upper respiratory viruses, dermatophytes, and coccidia are among the most difficult pathogenic agents to control because of their persistence in the environment through carrier states and/or resistance to environmental disinfection. in particular, upper respiratory disease is the most common endemic disease in cat populations and is impossible to completely prevent in an open population. feline herpes virus type (fhv- ) and feline calicivirus (fcv) have been implicated as the causes of most infections: both viruses induce persistent carrier states and are widespread in the cat population. cats that recover from fhv- remain latently infected and shed virus intermittently, especially following periods of stress. fcv carriers shed continuously for months to years following infection. a variety of other viral and bacterial pathogens may also contribute to feline upper respiratory disease, and bordetella, chlamydophila, and mycoplasma are problematic in some populations. feline infectious peritonitis (fip) is another disease that is nearly impossible to eradicate from a multicat environment, and sporadic cases can be expected to occur, especially in young cats. fortunately, proper wellness programs can greatly limit the incidence and severity of diseases, even for pathogens that are difficult to control. the multicat environment also presents enormous opportunities for inducing stress. because of their unique biology, cats are particularly prone to experiencing acute stress and fear in novel environments. anything unfamiliar to a cat can trigger apprehension, activating the stress response. confinement in a novel environment can result in a wide variety of behavioral indicators of stress including hypervigilance, feigned sleep, constant hiding, activity depression, and loss of appetite, among others. in the long term, if cats are unable to acclimate or cope in their environments, chronic stress, fear, frustration, or learned helplessness may result. in group settings, signs of social stress may also manifest with medical decisions must be weighed in the context of the health of the population as well that of the individual, while considering animal welfare and the availability of resources for care. when large numbers of animals are involved, situations may arise in which animal health and welfare cannot be managed in the case of every individual animal. this may be due to physical or behavioral illness, or environmental conditions that negatively impact animal health, such as crowding. regardless of the cause, it may be necessary to euthanize affected individuals if no other remedies exist to relieve animal suffering or to protect population health. these decisions can be difficult and emotionally challenging, especially in instances where the individual could easily be treated or otherwise accommodated if adequate resources were available. however, such decisions may be crucial for disease control, animal welfare, and population health. that being said, euthanasia should never be used as a substitute for providing proper husbandry and care. indeed, a critical need for a comprehensive wellness program exists in every multicat setting. it is unacceptable to house animals under conditions likely to induce illness and poor welfare, and such conditions can be expected when wellness programs are not in place and carefully monitored. when facilities elect to house cats with medical or behavioral problems, appropriate veterinary care must be provided. it is imperative that a humane plan for diagnosis, treatment/management, monitoring, and housing be implemented in a timely fashion. when determining if cats with special needs can be humanely cared for in a population setting, the following goals and considerations should be addressed: what measures must be implemented to prevent transmission of disease to other cats or people? can appropriate care realistically be delivered? will the care provided result in a cure or adequate management of the disease or problem behavior? can the facility afford the cost and time for care? how will it impact resources available for other cats? in the case of animal shelters, additional considerations should include will the cat be adoptable? what steps can be taken to minimize the holding time required for treatment? if the cat is not adopted, do humane long-term care options exist in the shelter? what welfare assessment will be used to measure quality of life in the shelter? disease control efforts when disease is present. however, the best method of disease control is always prevention. when creating preventive medicine programs for a population, consideration must be given to all components of wellness: physical, behavioral, and environmental health. with regard to promoting physical health, wellness programs should address the following essential elements: implementing population wellness protocols and ensuring quality and timely care require reliable systems for medical record keeping and animal identification. regardless of the system used, medical record keeping procedures should comply with state and local practice acts, guidelines provided by state and national veterinary medical associations, and, in the case of laboratory animals, regulations as prescribed by federal law, the increases in problem behaviors, including urine marking, spraying, or other inappropriate elimination; constant hiding; and/or aggression. stress not only has the potential to negatively impact behavioral health but also physical health as well. the intimate link between stress and immunity has been well described. in fact, stress is a leading factor in the development of infectious disease and is particularly important in the pathogenesis of feline upper respiratory infections. , wellness programs that reduce stress will also serve to minimize the morbidity of infectious disease. despite the fact that infectious agents can never be completely eliminated from the environment, it is still possible to maintain good health. this is because the development of disease is determined by a complex interaction of many factors surrounding the host, the infectious agent, and the environment. keeping these factors in mind provides a rational context for many of the recommendations in this chapter. some of the host factors that influence health and the development of disease include age, sex and reproductive status, immune status, body condition, stress, and genetics. the amount and duration of exposure to an infectious agent (i.e., the "dose effect"), as well as its virulence and route of inoculation, also influence the likelihood and severity of disease. in addition, environmental conditions contribute to the development of infectious disease, including such factors as housing density, sanitation, and fluctuations in temperature or air quality. the fact that disease results from such a large combination of factors underscores the importance of a holistic and broad-based approach to population wellness. when infectious disease does occur in a population, general principles of infectious disease control should guide the response. these include . some facilities prefer to use safety collars that are designed to break away should the collar become caught on something. even for kittens, collars can be used and may be especially beneficial, because they will learn to wear them from an early age. microchips may also be used for identification and are safe and simple to implant (figure - ) . the procedure is well tolerated by the vast majority of cats without the need for sedation. unlike visual means of identification, a scanner is necessary for positive identification of a microchipped animal. for this reason, microchips are often used in conjunction with a visual means of identification and serve as important permanent means of backup identification. box - describes the proper technique for scanning for a microchip. during the last decades, microchips of varying radiofrequencies ( , , and khz) have been introduced in the united states. the -khz chips have historically been the most common, whereas the accepted standard in the rest of the world is the -khz chip. because some scanners read only certain radiofrequencies, it is possible to miss detecting a microchip that is present, depending on the scanner being used. currently, there are efforts to standardize microchipping in the united states, including widespread distribution of universal (global) scanners to ensure that all implanted microchips can be reliably identified. once global scanners are widely available, the american veterinary medical association (avma) recommends adoption of the -khz (iso) microchip as the american standard, because this frequency is recognized as the international standard for microchips institute for laboratory animal research and institutional animal care and use committees. computerized records are preferred; however, written records may also be used. computerized records offer the advantage of mechanized reporting, which facilitates detection and monitoring of health trends in the population. a medical record should be prepared for each cat and should include the cat's entry date, identification (id) number, date of birth, gender, breed, and physical description, as well as historical and physical/behavioral examination findings. in addition, it should contain the dosages of all drugs administered and their routes of administration, including vaccines, parasite control products, other treatments, and anesthetic agents; the results of any diagnostic tests performed; any surgical procedure(s) performed; and other pertinent information regarding the animal's condition. standardized examination and operative reports may be used, but should allow for additions when necessary. identification of cats in the form of a neckband, collar and tag, tattoo, earband, and/or a microchip is also essential for preventive health care and ongoing surveillance of individuals. whenever possible, some form of identification should be physically affixed to every individual cat. in addition, enclosures should be labeled with the cats' unique identification number and/or name. contrary to popular belief, most cats can reliably wear collars safely and comfortably. many facilities use disposable collars, including commercially available plastic or paper neckbands made for animals or hospital-type wristbands made for human patients (figure - ). commercially available cat collars with an id tag affixed in the rest of the world. efforts have also focused on improving, updating, and centralizing microchip registries. this is extremely important in the context of animal shelters. box - contains information on the use of collars and microchips as tools for improving cat-owner reunification. in laboratory settings, tattoos may be used as a means of permanent identification of cats ( figure - ). tattoos are most commonly applied to the inner pinna of the ear using a tattoo machine with multiple needles. care must be taken to properly disinfect the needles between patients. a significant disadvantage of tattooing is that tattoos can sometimes be difficult to read because of the presence of hair, fading, or distortion that may occur as the cat grows. in addition, their application requires anesthesia or heavy sedation. small stainless steel ear tags manufactured for wing banding of birds are especially useful for identifying newborn kittens in some settings and are highly economical (figure - ). they can be placed without the need for anesthesia or sedation when kittens are less than to days old. placing earbands requires skill and experience. they must be positioned in such a way as to provide adequate space for growth of the ear, while seating them deeply enough in the ear margin to ensure a secure piercing far enough away from the edge. if placed too close to the ear margin, the ear flap may tear, resulting in loss of the band. other complications include local inflammation or infection at the site of the piercing. ear tags are a practical method for identifying individual kittens in institutional or commercial breeding colonies, because when applied skillfully, they are seldom lost and provide reliable, long-lasting visual identification. in contrast, private breeding catteries and animal shelters generally prefer to use methods that will not alter the cat's cosmetic appearance long term. colored ribbon, nail polish, or clipping of hair in various areas of the body can all be useful means of temporary kitten identification in the neonatal stage, especially when coat color or patterns do not easily allow individuals to be distinguished. every cat, including those surrendered by their owners, should be systematically scanned for the presence of a microchip at the time of intake, as well as prior to being made available for adoption or being euthanized. proper technique and scanning more than once are crucial to avoid missing microchips. , a universal (global) scanner (e.g., one that will read all microchip frequencies that are currently in use) should be used to ensure that all microchip frequencies are detected. at this time, the only universal scanners available in the united states are the new home again global world scanner (schering plough, whitehouse station, ny) and the imax black label resq scanner (bayer animal health, shawnee mission, kans.). one of the most common causes of scanner failure is weak batteries; therefore it is imperative that batteries be checked and replaced regularly. to ensure a thorough scan and avoid missing chips, cats must be removed from carriers or cages prior to scanning. metal and fluorescent lighting may interfere with chip detection. metal exam surfaces should be covered with a towel or other material prior to scanning to minimize interference. the entire animal should be scanned using a consistent speed, scanner orientation, scanning pattern, and distance. • scanner orientation: the scanner should be held parallel to the animal. rocking the scanner slightly from side to side will maximize the potential for optimal chip orientation and successful detection. the button on the scanner should be depressed continuously during the entire scanning procedure. • scanning distance: the scanner should be held in contact with the animal during scanning such that it is lightly touching the hair coat. • scanner speed: the scanner should not be advanced any faster than . m/second ( . ft/second). scanning slowly is crucial, because universal scanners must cycle through various modes to read all possible chip frequencies. • areas of animal to scan: the standard implant site is midway between the shoulder blades, and scanning should begin over this area. if a microchip is not detected here, scanning should proceed systematically down the back, on the sides, neck, and shoulders-all the way to the elbows in the front and the hindquarters in the rear. • scanning pattern: the scanner should be moved over the scanning areas in an "s"-shaped pattern in a transverse direction (from side to side). if no microchip is detected, the scanner should be rotated degrees, and then the "s"-shaped pattern should be repeated in a longitudinal direction (e.g., the long way) on both sides of the animal. this pattern of scanning will maximize the ability of the scanner to detect the microchip, regardless of its orientation. • less than % of cats are reunited with their owners, compared to as many as % to % of lost dogs. • the use of collars and tags as visually obvious forms of identification is extremely valuable, although overlooked by many cat owners. • cats wearing collars are more likely to be identified as owned and not mistaken for strays. • even indoor cats require identification in case they escape, and studies clearly demonstrate that visual identification improves the odds of pet-owner reunification. • the provision of permanent identification in the form of a microchip represents an important backup, further improving the odds of pet-owner reunification because collars and tags can be lost. • because owners and shelter staff often describe cat coat color and patterns differently, photographs that can be posted online are a useful method of improving lost-pet matching and enabling owners to look for their pet, even if they are physically unable to come to the shelter. • adopted animals should be sent home with id collars and microchips. • shelter staff should always register microchips before the cat leaves the shelter, because many owners will neglect to do so following adoption, making the microchip an ineffective means of identification. • web-based search engines for pet microchip identification numbers (http://www.checkthechip.com and http://www.petmicrochiplookup.org) have been established in an effort to functionally centralize microchip registries by linking existing national databases. facility that houses cats establish a formal relationship with one or more veterinarians who have direct knowledge of their animal population. this is essential to ensure that medical protocols are established with the proper professional oversight, and helps to ensure compliance with local veterinary practice acts that restrict the practice of veterinary medicine to licensed veterinarians. in facilities such as animal shelters, trained shelter staff can carry out preventive health care under the instructions of a veterinarian. the success or failure of a population wellness program hinges in large part on its implementation and oversight. a knowledgeable, cohesive, and dedicated team, where accountability, responsibility, and lines of authority are well defined, is crucial for management success. as a part of the management structure and plan, veterinarians must be involved in the oversight of all aspects of animal care and must be given direct authority for the oversight of medical decisions. this requires that every physical examination is the clinician's single most important tool for evaluating health. following a standardized physical examination form will ensure a complete and systematic review of all body systems. a veterinarian should carefully examine any new cat entering a closed population prior to admittance. in the context of animal shelters, every cat that is safe to handle should receive a physical examination at or as close to the time of admission to the shelter as possible. in many shelters, a veterinarian may not be available to examine incoming animals. however, staff can and should be trained to perform basic evaluations including sexing, aging, body condition scoring, and looking for evidence of fleas, ear mites, dental disease, overgrown claws, advanced pregnancy, or other obvious physical conditions. of particular importance in the shelter physical examination are an accurate physical description of the animal and careful inspection for the presence of identification, both of which may aid in pet-owner reunification. the gold standard for maintaining the health of a population is through exclusion of pathogens in combination with implementation of comprehensive wellness protocols. this requires that members of a population be free from specific pathogens when the group is established and that the colony be closed to any new individuals that do not meet the health standards of the group. this is the foundation of disease control procedures in a laboratory animal setting, and these concepts should be applied to other population settings whenever possible. consideration should be given to testing for the following: feline leukemia virus (felv), feline immunodeficiency virus (fiv), dermatophytosis, intestinal parasites and infections (e.g., campylobacter, giardia, coccidia), as well as other endoparasites and ectoparasites. the setting and resources available, as well as the individual's history and physical examination findings, should guide the clinician's decisions regarding selection of testing for cats entering a specific population. when new stock is added to a closed colony, disease testing is imperative. the american association of feline practitioners (aafp) maintains detailed professional guidelines for the management of felv and fiv infections. identification and exclusion of infected cats is the most effective method of preventing new infections. cats and kittens should always be tested prior to entry to a closed population. those that test negative should be retested, because it the clinician should develop a program for physical health for the population that addresses all of the essential elements as noted. none of these should be considered as optional, but their implementation will depend on the setting, purposes, and resources of the group. the value of obtaining an accurate medical history on any cat entering a population is immeasurable, because it will often alert the clinician to the presence of potential problems. in a laboratory setting, obtaining cats from commercial purpose-bred colonies or institutional breeding colonies ensures that an accurate history will be available, maximizing the odds that only healthy cats will be added to the population. likewise, private breeding catteries should always strive to obtain an accurate medical history on any cat that may be accepted into the cattery. the introduction of cats from random sources to closed populations of cats risks the health of the population and should be avoided whenever possible. in contrast, by their very nature, animal shelters must frequently receive cats from multiple random sources, and it will not always be possible to obtain accurate histories. in some cases, cats are brought in by animal control officers or good samaritans who have little if any information about them. furthermore, some shelters provide a location (e.g., drop-off cages) where cats can be relinquished after business hours. this practice should be discouraged; however, if facilities elect to do this, every effort must be made to obtain a history through questionnaires that can be completed when the cat is left. the presence of staff to directly accept cats and obtain a history at the time of relinquishment is greatly preferred. even so, surrendering owners may or may not provide complete or accurate information, fearing that if they are honest about a pet's problems, the pet may be euthanized. nonetheless, when available, a history can be extremely valuable, saving time and money as well as preventing unnecessary stress for cats and staff alike. intake procedures should be in place to capture basic patient information, including both physical and behavioral data as well as the reason(s) for relinquishment. the importance of obtaining historical information cannot be overemphasized. in many cases, historical information may be used to expedite the disposition of the cat in the shelter. can be problematic. in relation to population health, testing is of little value, because infected cats pose no risk to other cats. nonetheless, a clinician may elect testing as part of an initial database for individual cats, especially if they will be used for breeding. with heartworm tests readily available in combination with pointof-care felv/fiv tests, many animal shelters have been faced with determining whether or not to perform routine screening of cats in their care. to answer this question, it is helpful to consider the following: in consideration of these facts, the author does not recommend routine screening of cats for heartworm disease in shelters. monthly chemoprophylaxis, however, is a safe and effective option for cats sheltered in areas where heartworm infection is considered endemic. dermatophytosis or ringworm, the most common skin infection of cats, is a known zoonosis. it is caused by infection of the skin, hair, and nails with microscopic fungal organisms that cause varying degrees of hair loss and dermatitis. the dermatophyte that causes the majority of cases in felines is microsporum canis, which is responsible for greater than % of all cases. if left untreated, most infections will spontaneously resolve within to weeks postinfection. however, during this time, the infected cat will infect the surrounding environment and other animals or humans in the area. not all cats infected with dermatophytosis develop lesions, and some may become chronic carriers. control of dermatophytosis is difficult, because the spores formed by m. canis can survive in the environment for up to months or longer and are extremely resistant to disinfectants and detergents. in addition, the presence of asymptomatic carriers makes it difficult to readily recognize all infected cats. for this reason, consideration should be given to culturing all cats prior to entry to a closed colony. in particular, persian cats may be predisposed to dermatophyte infection and can be particularly difficult to clear once infected. in closed colony settings, dermatophyte testing by culture is highly recommended unless the source of the cat excludes the possibility of infection (e.g., specific pathogen-free [spf] cats, purposebred laboratory cats). to screen cats using cultures, may take as long as days following exposure for a cat to test positive. , in the context of animal shelters, testing decisions are often influenced by the availability of resources. the aafp's guidelines include recommendations specifically for shelters. they state that all cats should ideally be tested at the time of entry and again in days in case of recent exposure. when cats test positive on screening tests (e.g., point-of-care enzyme-linked immunosorbent assay [elisa] tests), the aafp recommends that the results be confirmed by additional testing, including testing over an interval of time, because false positives can occur. however, such confirmatory testing requires substantial time and monetary investment and may not be feasible in many shelters. in recognition of this, the association of shelter veterinarians established a policy statement on "management of cats who test positive for felv and fiv in an animal shelter," which states that the logistics and cost of holding and retesting unowned cats may be an ineffective use of resources. in addition, it can be difficult to find homes for retroviruspositive cats, which in many instances translates into stressful, prolonged shelter stays. such long-term confinement may compromise quality of life and may compound the emotional stress of caregivers who may later be faced with euthanizing cats that have been held for long periods awaiting confirmatory testing or adoption opportunities. for all of these reasons, many shelters elect to euthanize cats that test positive on retrovirus screening tests. although it may be ideal for shelters to test cats on entry, it is not always feasible because of financial constraints. the next best practice might be to test cats prior to adoption as well as those that are housed in the shelter long term. in addition, cats should be tested prior to placement in group housing with unfamiliar cats and prior to investment, such as foster care, treatment, or spay/neuter surgery. however, given the limited resources of many shelters, the relatively low prevalence in healthy cats and the fact that transmission can be prevented by housing cats separately, it may not be cost effective for all shelters to screen every cat before selection for adoption. each shelter should evaluate its own resources and determine their best use. when testing is performed, samples must never be pooled, and the negative results of one cat (such as a mother cat) should not be extrapolated to other cats (such as her kittens). these practices are invalid and can falsely lead to misidentification of a cat's true infection status. , if testing is not performed prior to adoption, adopters should be advised to have their new pet tested and to keep them separate from any other cats they may own prior to doing so. point-of-care heartworm tests for cats have recently become more widely available, but interpreting results vaccination protocols are typically applied uniformly to all of the individuals comprising the population. this simplifies their application and helps to afford the best possible protection for the group. detailed vaccination records should be maintained for each cat, including vaccine name, manufacturer and serial number, date, the initials of the person who administered it, and any adverse reactions. proper vaccination can substantially reduce disease in cat populations, and serious adverse reactions are relatively rare. for this reason, vaccination against certain core diseases is recommended in all population settings. although exclusion of infectious disease is always a goal of health management, certain pathogens are so widespread that even with careful biosecurity in a closed population, an infection may be introduced to susceptible cats. only in the case of specific pathogen-free colonies, where there may be a compelling reason not to vaccinate as dictated by the purposes of the research, should vaccination be foregone. the aafp maintains published guidelines for vaccination of cats in a variety of settings and includes detailed recommendations for cats in animal shelters. although many vaccines are commercially available for cats, only a few are recommended for routine use in populations. unnecessary use of vaccines should be avoided to minimize the incidence of adverse reactions and reduce cost. core vaccines involve diseases that represent significant morbidity and mortality and for which vaccination has been demonstrated to provide relatively good protection against disease. core vaccines for cats in a population setting include feline parvovirus (fpv or panleukopenia), fhv- (feline herpes virus type or feline rhinotracheitis virus), and feline calicivirus (fcv). these vaccines are usually given in a combination product commonly referred to as an fvrcp vaccine (feline viral rhinotracheitis, calicivirus, panleukopenia). in most cases, timely vaccination against panleukopenia will prevent the development of clinical disease. in contrast, vaccination against the respiratory viruses (fhv- and fcv) does not always prevent disease. in many instances, it affords only partial protection, lessening the severity of clinical signs but not preventing infection. to optimize response, modified live vaccines (mlv) should be used in most cases, because they evoke a more rapid and robust immune response and are better at overcoming maternal antibody interference than killed products. this is especially important in multicat environments in which the risk of infection is high, such as animal shelters, foster homes, as well as any population setting where upper respiratory disease is endemic. a samples should be collected using the mckenzie toothbrush method, where a new toothbrush is used to brush the cat's entire body, giving special attention to the face, ears, and limbs. in addition, if skin lesions are present, hair should be plucked around these areas for culture as well. campylobacter, salmonella, giardia, coccidia, tritrichomonas, and other gastrointestinal parasites and pathogens are common in some cattery situations and can be very difficult to eliminate once they are introduced. in fact, in some settings, these pathogens may become endemic and nearly impossible to eliminate. treatment of coccidia in shelter kittens is described in although clinical signs, such as diarrhea, may be associated with infection, some cats remain asymptomatic. these pathogens have the potential for high morbidity in a population (especially in young kittens), and some possess zoonotic potential. therefore routine fecal examinations, cultures, and/or empirical treatments should be considered prior to the introduction of new cats. it is well recognized that vaccination plays a vital role in the prevention and control of infectious diseases. protocols should be established in the context of the population's exposure risk, which will vary depending upon the setting. in the context of population medicine, ponazuril is a metabolite of toltrazuril that has proven activity against coccidia.* because there is no approved product for use in cats, the equine product marquis oral paste ( % w/w ponazuril; bayer healthcare) may be dosed at mg/kg, po, once daily for to days. prophylactic treatment may be instituted in high-risk situations, such as young kittens in environments with documented infection. proper hygiene, including the use of disposable litter boxes and frequent removal of feces, is also necessary. oocysts survive in the environment and are not treated by routine disinfectants, such as bleach and quaternary ammonium compounds. with a history of upper respiratory infection) may benefit from vaccination prior to breeding to maximize passage of maternal antibody to their kittens. for pregnant cats in such environments, administration of mlv should be avoided, because the potential risk of injury to the developing kittens may outweigh the risk of infection in this case. vaccination of lactating queens should also be avoided in a low-risk environment. a series of vaccinations should be administered to kittens less than months of age to minimize the window of susceptibility to infection and ensure that a vaccine is received as soon as possible after maternal antibodies have decreased sufficiently to allow vaccine response. for kittens, vaccines should be administered every to weeks until they are weeks (e.g., months) of age or their permanent incisors have erupted. the minimum interval of weeks is recommended in high-risk settings to narrow the window of susceptibility as maternal antibody wanes. a vaccination interval of less than weeks is not recommended, because it may actually blunt the immune response from previous vaccination. in the case of an outbreak of panleukopenia, extending vaccination to months of age may be warranted to ensure than no animal remains susceptible. although the vast majority will respond by months of age, a few may fail to respond, while others are provided with a boost to enhance the immune response. just as in owned pets, booster vaccines are generally not required until year later for modified live vaccines but should ideally be administered once in to weeks whenever resources permit. this may be especially important for cats that were ill at the time of initial vaccination, as may be the case in an animal shelter. revaccination in long-term shelter facilities should follow the guidelines set forth for pets: boost at one year, then every years for fvrcp. vaccination against rabies virus is regarded as a core requirement for pet cats and is required by law in some jurisdictions. thus vaccination against rabies is recommended in the context of private catteries. in contrast, rabies vaccination may be considered optional in most closed laboratory settings, because the risk of exposure should be absent and legal requirements may not apply. in animal shelters, vaccination against rabies is not generally recommended at the time of admission, simply because there is no benefit in terms of disease prevention or public health. vaccination on admission will not provide protection against an infection acquired prior to entry, nor will it limit concern if a cat with an unknown health history bites someone soon after admission. rabies vaccination is recommended for cats prior to adoption when a veterinarian is available to administer it (or as otherwise legally prescribed by state laws). alternatively, rabies vaccination may be administered as single modified live fvrcp vaccine will usually afford protection to cats that are at least months of age. in contrast, killed products require a booster in to weeks to confer immunity, making their use largely ineffective in such environments. to ensure rapid protection against panleukopenia, injectable fvrcp vaccines are preferred, but intranasal vaccines may offer advantages for feline respiratory disease, because they have been shown to rapidly induce local immunity at the site of exposure. furthermore, intranasal vaccines may be better at overriding maternal antibody in young kittens. for this reason, they are often used to reduce the morbidity and severity of upper respiratory infection (uri) in preweaningage kittens. when intranasal vaccines are used in animal shelters, they should be used in combination with injectable fvrcp vaccines to ensure and optimize response against panleukopenia as well as the respiratory infections. ideally, all cats should receive a mlv fvrcp vaccine at least week prior to entering a population. in the context of an animal shelter setting, this is seldom feasible. vaccination immediately upon entry is the next best practice and can provide clinically significant protection for the majority of cats. if neither maternal antibody nor another cause of vaccine failure interferes, modified live vaccinations against panleukopenia will often confer protection against disease in only days. intranasal vaccines against respiratory infections, including fhv and fcv, typically provide partial protection within to days. , in animal shelters, all incoming cats and kittens weeks of age and older that can be safely handled should receive an injectable mlv fvrcp vaccine immediately upon entry. a delay of even a day or two significantly compromises the vaccine's ability to provide timely protection. even injured cats, those with medical conditions, and those that are pregnant or lactating should be vaccinated on entry, because vaccination will likely be effective and the small risk of adverse effects is outweighed by the high risk of disease exposure and infection in the shelter. when vaccination of all cats on entry is not financially feasible, the next best practice is to vaccinate all those that are deemed adoptable at the time of entry or that are likely to be in the shelter long term. whenever possible, vaccinated cats should be separated from those that will remain unvaccinated (e.g., those that will be euthanized following a brief holding period) as soon as that determination can be made. in contrast, in lower-risk settings, ensuring that cats are in good health prior to vaccination should be a priority. vaccination of kittens with injectable fvrcp vaccinations may be delayed to to weeks of age. however, when respiratory disease is endemic, administration of intranasal vaccines beginning at weeks of age may be beneficial. in breeding catteries, queens (especially those control and prevention of internal and external parasites represent another important component of a population wellness program. common products used for their management are described elsewhere in this book. of particular importance are roundworms and hookworms, common intestinal parasites with zoonotic potential (see chapter ) . although uncommon, the risk of human infection from contaminated environments is real and can result in organ damage, blindness, and skin infections. for this reason, the centers for disease control and prevention and the companion animal parasite council strongly advise routine administration of broad-spectrum anthelminthics for their control. , pyrantel pamoate is one of the most costeffective and efficacious drugs for treatment and control of roundworms and hookworms. in both shelter and cattery settings, the author recommends administration of pyrantel pamoate at a dosage of mg/kg to all cats with re-treatment in weeks and then at monthly intervals. in shelters, if it is not possible to treat all cats at the time of entry, at a minimum, all cats that are deemed adoptable should be treated as soon as possible. in addition, kittens should be treated at -week intervals until months of age. for cats with diarrhea, fecal examination (e.g., flotation or centrifugation, direct fecal smear and cytology) should be performed with treatment according to results. even if results are negative, the administration of broad-spectrum anthelminthics should be strongly considered. in animal shelters, ectoparasites, particularly ear mites and fleas, are also very common in cats and kittens. shelter staff should be trained to recognize infestation and protocols should be established for treatment. in terms of shelter treatment protocols, the author recommends treating ear mites with ivermectin, because it is highly efficacious and costs only pennies per dose. the recommended dosage is . mg/kg subcutaneously. for fleas, the author recommends topical treatment with fipronil (frontline, merial, duluth, ga.) as a spray or top spot. in particular, the spray is very cost effective. it is safe for use in cats of all ages, including pregnant and nursing mothers and neonatal kittens. in addition, fipronil also has activity against ear mites, cheyetiella, chewing lice, and ticks. , spaying and neutering is another important consideration in the context of population wellness. reproductive stress from estrous cycling in queens and sex drive in tomcats can decrease appetite, increase urine spraying/ marking and intermale fighting, and profoundly increase social and emotional stress in the group. for these reasons, spaying and neutering cats that will not be used soon as possible following adoption. the latter may encourage new owners to establish a relationship with a private veterinarian. rabies vaccination is warranted when cats are housed long term in shelter facilities. in addition, if individual cats must be held for bite quarantines, they should be vaccinated against rabies in accordance with the current compendium of animal rabies prevention and control. noncore vaccines include those that may offer protection against disease, but because the disease in question is not widespread or only poses a risk of exposure in certain circumstances, vaccination is only recommended based on the individual risk assessment of a population of animals. noncore vaccines include felv, fiv, chlamydophila, and bordetella. vaccination against felv is not warranted in a closed population of cats in which there is no risk of exposure (e.g., most laboratory animal settings). in private catteries, a risk assessment should be done to determine if vaccination is warranted (e.g., cats permitted in outdoor enclosures, frequent introduction of cats from external sources, other opportunities for exposure). special consideration should be given to vaccinating kittens because of their high susceptibility to felv infection and the high likelihood that they will become persistently infected if exposed. in general, felv vaccination is not recommended in animal shelters when cats are housed short term. however, its use is warranted when cats are group housed when resources permit. fiv vaccination is not generally recommended in population environments. a confounding feature of fiv vaccination is that vaccinated cats develop false-positive test results on most commercially available tests (see chapter ) . if fiv vaccination is elected, vaccinated cats should be permanently identified (e.g., by use of a microchip) to help clarify their status. chlamydophila felis (c. psittaci) and bordetella bronchiseptica vaccines may be of benefit when clinical signs of these diseases are present in the population and diagnosis is confirmed by laboratory evaluation. their efficacy is moderate, and reactions are more common than with most other feline vaccines; therefore ongoing use should be periodically reassessed. some vaccines are not generally recommended for use because of undemonstrated efficacy, such as the feline infectious peritonitis (fip) vaccine. wants whenever he or she chooses. dry food is used for this method of feeding, because canned products left at room temperature are prone to spoiling. the major advantage of free choice feeding is that it is quick and easy: caregivers simply need to ensure that fresh dry food is always available. major disadvantages include the fact that cats that are not eating may remain unrecognized for several days, especially when more than one animal is fed together, and some cats may choose to continually overeat and become obese. free choice feeding is an excellent method for cats that require frequent food consumption. these include kittens up to to months of age, queens in late gestation, and those that are nursing. unlike dogs, who are competitive eaters by nature, free choice feeding may benefit cats that are group housed, because it ensures that there will be ample time for all members to eat, provided that dominant members of the colony do not block the access of subordinate cats. meal feeding using controlled portions of dry and/or canned food may be done as an alternative to or in conjunction with free choice feeding. when used alone, a minimum of two meals should be fed per day. meal feeding is ideal for any cat that requires controlled food intake and facilitates monitoring of appetite. meal feeding also has the benefit of enhancing caregiver-cat bonding and provides a pleasant and predictable experience for cats when done on a regular daily schedule. using a combination of free choice plus once daily meal feeding takes advantage of the positive aspects of both methods and works well for most cats in a population setting. typically, dry food is available free choice, and a small meal of canned food is offered once daily. this combination approach accommodates the normal feeding behavior of cats by allowing them to eat several smaller meals throughout the day while allowing caregivers to monitor the cat's appetite at least for the canned food meal. as necessary for the individual cat, some may be fed additional meals of canned food to ensure adequate nutritional support. good body weight and condition and a healthy hair coat are evidence of an adequate nutritional plane and proper nutritional management. both appetite and stool quality should be monitored daily. normal stools should be well-formed and medium to dark brown. adult cats typically defecate once daily, although healthy adults may defecate anywhere between twice a day and twice a week. kittens tend to produce a larger volume of stool more frequently, which is often lighter in color and softer in form than that of adults. simple scales can be used for monitoring appetite (e.g., good, some, none), and fecal scoring charts are available. the author recommends the purina fecal scoring system chart available from nestlé purina petcare company (figure - ) . for breeding is recommended. in animal shelters, spaying and neutering cats prior to adoption will ensure that they do not reproduce and contribute to the surplus of community cats. this will also serve to enhance husbandry, because the procedures rapidly decrease spraying, marking, and fighting; eliminate heat behavior and pregnancy; and greatly mitigate stress. in addition to reducing stress and odor, spaying and neutering sexually mature cats will facilitate group housing, which is often beneficial for cats, especially when housed longer term (see below). the medical benefits of spay/neuter have also been well described, including dramatic reductions in the risk of mammary carcinoma, elimination of cystic endometrial hyperplasia, pyometra and ovarian cancer in queens, and decreased risk of prostate disease in toms. thus spaying and neutering favors both individual as well as population health. proper nutrition has a profound impact on wellness. not only is it essential for management of healthy body weight and condition, good nutrition is also known to support immune function. a regular diet of palatable commercial food consistent with life stage should be offered, and fresh water must always be available. although some cats tolerate changes in food without apparent problems, it is important to recognize that for others, changing from one diet to another can cause loss of appetite and/or gastrointestinal upset. for this reason, it is generally best to provide the most consistent diet possible. whereas this may be relatively easy to do in a laboratory or cattery setting, it can be more challenging in a shelter environment. some pet food companies offer feeding programs for animal shelters, providing a consistent food for purchase at a special rate for shelters. however, some shelters rely heavily on donations of food. in this case, by requesting donation of certain brands of food, shelters are able to provide a consistent diet whenever possible. it is also feasible to mix donated foods with the shelter's usual diet to minimize problems caused by abrupt diet changes while taking advantage of other donated products. the wild ancestors of domestic cats hunted to eat, feeding up to times in a -hour period. this style of feeding behavior is preferred by many domestic cats that would nibble throughout the day and night, consuming many small meals if left to their own devices. although this is true, most cats are capable of adapting to either free choice or meal feeding as their daily feeding pattern. , there are advantages and disadvantages to each in a population setting. with free choice or ad libitum feeding, food is always available such that a cat can eat as much as he or she trends in body weight, because both weight loss and gain can compromise health and well-being. appropriate grooming is also essential to ensure wellness and must never be considered as optional or purely cosmetic. most cats require minimal grooming because of their fastidious nature. however, long-haired cats are notable exceptions, often experiencing matting of the hair coat without regular grooming sessions. matted hair coats are not only uncomfortable for the animal, but may lead to skin infection. overgrown nails can also be a problem for some cats, particularly those that are geriatric or polydactyl. the provision of appropriate surfaces for scratching will encourage cats to condition their own claws; and a system for regular inspection of the hair coat and nails should be established. in addition to ensuring proper coat and nail maintenance, regular grooming sessions provide an excellent opportunity to monitor body condition; and some cats enjoy the physical contact and attention. in high-risk settings, the use of stainless steel combs or undercoat rakes that can be readily disinfected are generally preferable to the use of in addition to appetite and stool quality, it is essential to monitor body weight and condition. body condition can be subjectively assessed by a process called body condition scoring, which involves assessing fat stores and, to a lesser extent, muscle mass. fat cover is evaluated over the ribs, down the top line, tail base, and along the ventral abdomen and inguinal (groin) areas. body condition score charts have been established on scales of to and to . the author recommends use of the purina body condition score chart which is based on a scale of to with being emaciated and being severely obese (see figure - ). cats should be weighed and their body condition scored at routine intervals. ideally, body weight should be recorded at entry to the population and then weekly during the initial month of care, after which it could be recorded once a month or more often as indicated based on the individual's condition. this is especially important for cats, because significant or even dramatic weight loss may be associated with stress or illness during the first few weeks of confinement in a new setting. on the other hand, in long-term-housed cats, excessive weight gain may occur in some individuals. therefore protocols must be in place to identify and manage unhealthy score -very moist (soggy); distinct log shape visible; leaves residue and loses form when picked up. score -very moist but has distinct shape; present in piles rather than as distinct logs; leaves residue and loses form when picked up. score -has texture, but no defined shape; occurs as piles or as spots; leaves residue when picked up. score -watery, no texture, flat; occurs as puddles. score -firm, but not hard; should be pliable; segmented appearance; little or no residue left on ground when picked up. score -log-like; little or no segmentation visible; moist surface; leaves residue, but holds form when picked up. fecal scoring system bristle brushes because the latter are impossible to disinfect and have the potential to spread common skin infections such as ringworm. dental health is another component of wellness. in the context of population wellness, it may not be the highest priority; however, it should always be a consideration in terms of individual health care and well-being. this is important because periodontal disease will occur unless it is actively prevented, and plaque and tartar buildup may contribute to serious health concerns, ranging from oral pain to chronic intermittent bacteremia and organ failure. feline tooth resorption and gingivostomatitis are also common conditions of the feline oral cavity that can lead to chronic pain, affecting the cat's appetite and ability to self-groom, and negatively impacting quality of life. when painful dental disease is present, a plan for timely treatment should be identified and implemented. preventive dental care may include tooth brushing, dental-friendly diets, and treats and chew toys in combination with periodic professional dental care. these should be tailored to meet the needs of individuals in the population to optimize dental health. cats with stomatitis should be removed from breeding programs. wellness protocols may also be dictated by the specific needs of certain breeds of cats. for example, persian, himalayan, and other brachycephalic cats are predisposed to respiratory disease and tend to be more severely affected than other cats because of their poor airway conformation. because of the high likelihood of exposure in a shelter setting, these cats should be housed in highly biosecure areas that are well ventilated and should be prioritized for immediate adoption or transfer to foster care or rescue. in the author's experience, even intranasal vaccination of these breeds can result in severe clinical signs of respiratory disease and is best avoided. just as a physical wellness program must be tailored to the population in question, a behavioral wellness program, composed of all of the essential elements, should be created to meet its specific needs as well. even when animals will only be housed for short periods, considerations for behavioral care are essential to ensure humane care. short-term confinement can induce severe stress and anxiety, and when confined long term, cats may suffer from social isolation, inadequate mental stimulation, and lack of exercise. a behavioral wellness program should strive to decrease stress from the moment cats arrive at a facility until the moment that their stay ends. as previously described, a thorough behavioral history will provide an important baseline for action and follow-up. understanding the importance of minimizing stress in cats and possessing the ability to recognize and respond to it are essential to facilitate a cat's transition into a population. , staff should be trained to evaluate cats beginning at intake and to recognize and respond to indicators of stress. active daily monitoring of cats for signs of stress or adjustment should be performed, and staff should record their findings daily, noting trends and making adjustments in the care of individual cats and the population as indicated. in animal shelter environments, proper behavioral care of cats also requires an understanding of the wide spectrum of feline lifestyles and an approach tailored to the individual needs of each group. domestic cat lifestyles and levels of tractability range from the most docile, sociable housecat, to free-roaming strays and truly unsocialized feral cats that will not allow handling. stray cats include those that may have been previously owned or are "loosely owned" neighborhood or barn cats. because of their lack of socialization, capture, handling, and confinement are especially stressful for feral cats. however, fearful cats may resort to overt aggressive or may "teeter on the edge" of defensive aggression regardless of their socialization status. in fact, even the tamest house cats may exhibit the same behaviors as feral cats when they are highly stressed (figure - ) . , these responses can compromise cat welfare and staff safety and hinder adaptation to a new environment. regardless of their demeanor, all cats and kittens should be provided with a hiding box in their enclosure at the time of entry, because the ability to hide has been shown to substantially reduce feline stress. for those cats that are severely stressed or reactive, covering the cage front, in addition to providing a hiding box, and posting signage to allow the cat "chill out" time for several hours or even a few days can facilitate adaptation. this is important because, once highly stressed or provoked, cats often remain reactive for a prolonged time and may become more reactive if they are stimulated again before they have been allowed a period of time to calm down. soft bedding should be available for comfort and so that cats may establish a familiar scent, which aides in acclimation to a new environment. care should be taken during cleaning procedures to minimize stress and noise, behavioral evaluation may be useful, especially for cats that will be re-homed. several evaluations have been recommended, but none are scientifically validated for predicting future behavior with certainty. , , nonetheless, this form of evaluation may be useful for determining behavioral needs while cats remain in a facility, as well as guiding appropriate placement. box - describes common components of a feline behavioral evaluation (figure - ) . housing design and operation can literally make or break the health of a population. regardless of the species in question, housing should always include a comfortable resting area and allow animals to engage in species-typical behaviors while ensuring freedom from fear and distress. it is not sufficient for the design to address only an animal's physical needs (e.g., shelter, warmth). it must meet their behavioral needs as well, and both the structural and social environment are essential considerations for housing arrangements. furthermore, the environment must provide opportunities for both physical and mental stimulation, which become increasingly important as length of stay increases. a sense of control over conditions is well recognized as one of the most critical needs for behavioral health. thus housing design must provide cats with a variety of satisfying behavioral options. specifically, housing arrangements must take into account the following feline behavioral needs : • opportunities for social interactions with humans and/or other compatible cats and cats should be allowed to hide while their cage is quietly tidied and replenished around them as needed. commercially available "cat dens" are ideal for this purpose, because they can be secured from a safe distance such that the cat is closed inside a secure, familiar hiding place during cleaning procedures (figure - ) . cats should be returned to the same cage and only spot cleaning should be performed to preserve their scent, which is necessary for stress reduction. if it becomes necessary to house the cat in another location, the den and towel should accompany the cat to ease the transition. finally, the use of commercially available synthetic analogues of naturally occurring feline facial pheromones (feliway, veterinary product laboratories, phoenix, ariz.) have been shown to be useful for stress reduction in cats during acclimation to new environments and can be sprayed onto bedding and allowed to dry prior to use or dispersed in the room using plug-in diffusers. the way in which cats are handled at intake has a profound impact on their behavior, health, and wellbeing and will impact the cat's ability to adapt to its new environment. when stress is successfully mitigated, cats are more likely to adapt and to "show their true colors" rather than reacting defensively. during a period of a few days, many cats that did not appear to be "friendly" at intake will become tractable and responsive to their human caregivers, facilitating care. aside from informally "getting to know" cats during their initial acclimation period in a facility, a systematic • the ability to create different functional areas in the living environments for elimination, resting, and eating • the ability to hide in a secure place • the ability to rest/sleep without being disturbed • the ability to change locations within the environment, including using vertical space for perching • the ability to regulate body temperature by moving to warmer or cooler surfaces in the environment • the ability to scratch (which is necessary for claw health and stretching, as well as visual and scent marking) • the ability to play and exercise at will • the ability to acquire mental stimulation because these needs will vary depending upon such factors as life stage, personality, and prior socialization and experience, facilities should maintain a variety of housing styles in order to meet the individual needs of different cats in the population (figure - ) . managing housing arrangements for a population of cats of varying ages, genders, personality types, social experiences, and stress levels requires knowledge of normal feline social behavior and communication. during the past decades, knowledge of feline social structure has evolved from the widespread belief that cats are generally an asocial and solitary species to the realization that they are social creatures. , with the exception of solitary hunting, free-roaming cats perform responses are observed and recorded for each of the following: • the tester approaches cage, stands quietly for seconds, then offers verbal encouragement. • if deemed safe to proceed, tester opens the cage door and calmly extends an open hand towards the cat, then attempts to gently touch the cat's head. • if the caregiver is unsure if this is safe to do, a plastic hand may be used to gauge the cat's receptiveness to touch (see figure - ). • if the cat allows handling, the cat is gently lifted and carried to a secure, quiet room for further observation. • the tester sits quietly on a chair and/or the floor; the tester calls and solicits the cat's attention. • the tester pets the cat on the head. • the tester strokes the cat down the back several times. • the tester picks up the cat and hugs it for seconds. • with the cat standing on the floor, the tester strokes the cat down the back and firmly but gently grasps the base of the tail and lifts the cat off of its hind feet for second. the tester repeats this a second time. • the tester engages the cat in play with an interactive toy. in some instances, it is difficult to determine if a cat will accept handling. to prevent injury to staff, a plastic hand (assess-a-hands; great dog productions, accord, ny) is used to approach this cat. as the hand approaches, the cat appears tense (a) but begins to relax and accepts petting (b and c) . the absence of normal behaviors (e.g., grooming, eating, sleeping, eliminating, stretching, greeting people). defensive behavior may involve characteristic postural and/or vocal responses, and is usually motivated by fear. disruptive behavior involves destruction of cage contents and creation of a hiding place. stereotypic behaviors (e.g., repetitive pacing, pawing, and circling) may also develop as a result of stress but generally occur less commonly. as an illustration of these feline behaviors, consider the responses of a typical social domestic cat when caged in a novel environment (box - and figures - to - ) . behavioral signs of stress may be further classified as active communication signals or passive behaviors. , signals of anxiety, fear, aggression, and submission may be subtle or obvious and include vocalization (growling, hissing), visual cues (facial expression, posturing of the body, ears, and tail), and scent marking (urine, feces, various glands of the skin). passive signs of stress include the inability to rest/ sleep, feigned sleep, poor appetite, constant hiding, absence of grooming, activity depression (decreased play and exploratory behavior), and social withdrawal. high-density housing exacerbates these signs. lowsocial-order cats in such an environment may exhibit decreased grooming, poor appetite, and silent estrus. cats that are consistently fearful or anxious may hide, most of their activities within stable social groups where cooperative defense, cooperative care of young, and a variety of affiliative behaviors are practiced. affiliative behaviors are those that facilitate close proximity or contact. cats within groups commonly practice mutual grooming and allorubbing (e.g., rubbing heads and faces together). this may serve as a greeting or as an exchange of odor for recognition, familiarization, marking, or development of a communal scent. cats of both genders and all ages may exhibit affiliative behaviors, and bonded housemates often spend a large proportion of their time in close proximity to one another. maternal behavior is the primary social pattern of the female cat, and cooperative nursing and kitten care are common. if allowed, queens form social groups along with their kittens and juvenile offspring. , tomcats typically reside within one group or roam between a few established groups. within groups of cats, a social hierarchy or "pecking order" forms. , once established, this hierarchy helps to support peaceful co-existence of cats within a stable group, minimizing agonistic behaviors between members. social hierarchy formation occurs within groups of cats that are sexually intact, as well as in those that are neutered. knowledge of behavioral signaling is critical for successful management of housing arrangements. manifestations of both normal and abnormal behavior indicate how successfully an animal is coping with its environment. common behavioral expressions of feline anxiety may manifest with inhibited or withdrawal behavior, defensive behavior or disruptive behavior. , inhibited or withdrawal behavior refers to activity depression or • fear is typically the initial response, and if threatened by the proximity of unfamiliar caregivers, defensive aggression may be displayed. alternatively, the cat may freeze or appear catatonic. • if provided with a box for concealment, the cat will hide or otherwise slink against the back of the enclosure, behind the litter box, or disrupt the cage and hide under the paper. • given time, most cats become more active and engage in greeting behaviors, coming to the front of the cage and pawing or mewing as caregivers approach. • if the cat remains confined with time without adequate periods of exercise, mental stimulation, and social companionship, stress and frustration will manifest with activity depression and withdrawal (lying in the litter box, failure to groom, failure to greet caregivers, and, in some cases, displaying aggression towards caregivers). • displays of stereotypic behavior (such as pacing) may occur; however, inhibited or withdrawal behaviors are much more common (see unfamiliar or new cats entering the group. within an established group, however, most social conflicts are not characterized by overt aggression. instead, the main mode of conflict resolution is avoidance or deference (figure - ) . , , deference behaviors include looking away, lowering the ears slightly, turning the head away, and leaning backward. large numbers of cats peacefully co-exist together, using such strategies for avoidance provided ample space and resources are available for all members of the group. signs of social stress within groups of cats may manifest with overt aggression, increased spraying and turn their back, huddle, and avert their eyes from the gaze of other cats. hiding is a normal and important coping behavior; however, when hiding is occurring with increased frequency or in response to stimuli that did not previously cause hiding, it should be recognized as a sign of stress. , in group settings, the complexity of the social structure cannot be overestimated. the internal structure of social groups rarely represents a straightforward linear hierarchy, except in very small groups of less than four to five animals. in larger groups of cats, there are usually one or two top-ranking individuals and one or two obvious subordinates, while the remaining cats share the middle space. , most cats within the group form affiliative or friendly relationships; however, some may fail to form such relationships and remain solitary. colony members commonly display aggression toward c marking, or constant hiding. , lower-ranking cats may spend little time on the floor, remaining isolated on single perches or other locations where they may even eliminate, while higher-ranking cats remain more mobile, controlling access to food, water, and litter resources. high-density housing conditions frequently result in such abnormal behaviors and are associated with increases in transmission of infectious diseases and reproductive failure as well. cats are commonly housed in three basic arrangements: cage or condo units, multiple runs within a room, or free ranging in a room. cage housing of cats should be avoided unless necessary for short periods for intake observation, legal holding periods in shelters as required by local ordinances, medical treatment or recovery, or to permit sample collection. although space recommendations vary substantially in the literature, common sense dictates that a determination of necessary housing space should take into account the cat's length of stay. in the author's opinion, it is neither appropriate nor humane to house cats in traditional cage housing long term (e.g., more than to weeks). the design of short-term housing should include provisions for housing individual animals, litters, families, or bonded housemates for intake evaluation and triage. housing must be easy to clean and sanitize, well ventilated, and safe for animals and caregivers. short-term housing should provide sufficient space to comfortably stand, stretch, and walk several steps; sit or lay at full body length; and separate elimination, feeding, and resting areas. litter boxes should be of appropriate size to comfortably accommodate the cats for which they are intended ( figure - ) . resting areas should include comfortable surfaces, soft bedding, and a secure hiding place to provide a safe refuge. a hiding place is essential, because it reduces stress by allowing cats to "escape," facilitating adaptation to a new environment. the addition of a sturdy box to a cage will provide a hiding place as well as a perch (figures - and - ) . in addition, cages should be elevated off of the floor by at least . m ( . feet), because this serves to reduce stress as well. in most instances, cage or condo style housing is used in most facilities for short-term holding at intake for observation, acclimation, and/or triage. runs or small rooms are also appropriate for intake housing, and offer cats the obvious benefit of additional space to meet their behavioral needs (figure - ) . regardless of their configuration, enclosures for short-term housing of cats should be large enough to allow them to stretch, groom, and move about while maintaining separate functional areas, at least . m ( feet) apart, for sleeping, eating, and elimination. , , laboratory guidelines in the united states call for a minimum floor area of . m ( ft ) for cats weighing less than kg and . m ( ft ) for cats weighing kg or more, with a minimum height . m ( ft). a resting upper respiratory infections. double-sided enclosures (e.g., cat condos) are ideal for meeting these specifications and have the benefit of easily allowing cats to remain securely in one side of the enclosure while the opposite side is cleaned (figure - ) . this helps to minimize stress, prevent exposure to infectious disease, perch is also required. current guidelines (european convention for the protection of vertebrate animals used for experimental and other scientific purposes, ets ) promulgated by the council of europe (http:// www.coe.int) for laboratory cats are similar, but proposed revisions call for substantially more floor space for cats, at . m ( . ft ) per adult cat with a height of at least m ( . ft). , the revisions, which have not been approved to date, also call for the provision of shelves, a box-style bed, and a vertical scratching surface. animal shelter facilities in the united states have traditionally been equipped with small perchless cages (e.g., . to . m or . to . ft long) that are poorly designed for housing cats. the association of shelter veterinarians (http://www.sheltervet.org) recommends a minimum enclosure size of m ( ft ) for adult cats. commercially available cages are typically approximately . m ( . ft) deep (e.g., an arm-length deep so that they can be readily accessed); therefore a cage with a length of . m ( ft) is required to provide this approximate square footage, and it will also allow for adequate separation of food, water, and litter ( figure - ) . similarly, the cat fanciers' association (http:// www.cfa.org) recommends a minimum of . m ( ft ) of space per cat for those weighing kg or more. cubic measurements take into account the use of vertical space in addition to floor space, which is crucial for improving the quality of the environment. for example, a . -m ( - larger enclosures also allow for better air circulation, which is an important consideration for control of feline housing for a single cat. note the large -ft long cage, provision of a secure hiding place and perch with bed, separation of litter from resting and feeding areas, and appropriately sized litter box for this large cat. housing units are available for cats and serve to separate functional living areas and provide improved opportunities for exercise and exploration. this unit (tristar metals, boyd, tex.) is constructed of powder-coated stainless steel, which is highly durable and easy to disinfect but less noisy than uncoated stainless steel. note the elevation from the floor and the grills on both the front and back, which allows flow-through ventilation. is both mentally and physically stimulating for cats and preferably that which is esthetically pleasing to humans. the latter is an important consideration to facilitate adoption in animal shelters. and, even in other types of facilities, it is important to create a pleasant environment not only for the animals, but also for their caregivers. studies indicate that employee satisfaction improves animal care and staff retention, both of which may positively impact population health and well-being. for long-term housing of cats alternatives to traditional cage housing should be afforded. , , at an absolute minimum, cats that are cage housed must be released each day and allowed an opportunity to exercise and explore in a secure enriched setting. for long-term housing, most cats will benefit from colony-style housing, provided there is sufficient space, easy access to feeding and elimination areas, an adequate number of comfortable hiding, and resting places and careful grouping and monitoring to ensure social compatibility among cats. not every cat, however, will thrive in a group setting, and certain individuals will require enriched single housing, depending on their unique physical or behavioral needs. these may include cats that bully other cats or are otherwise incompatible and those with special medical needs. it is important to recognize that such singly housed cats will require more regular contact with their human caregivers and higher levels of mental and physical stimulation in order to maintain behavioral health during long-term confinement. whenever possible, long-term housing of such individuals should be avoided. when cats are housed in amicable groups, it is easier to maintain proper behavioral welfare in the long term, because many of their social and emotional needs can be met by conspecifics. group housing affords cats with opportunities for healthy social contact with others, which, in turn, provides additional mental and physical stimulation. when properly managed, this housing arrangement enhances welfare.* insufficient space and crowding or poor compatibility matching of cats serves to increase stress and negates the benefits of the colony environment. group housing should never be used as a means of simply expanding the holding capacity of a facility. in animal shelters, the high turnover rate of cats contributes substantially to feline stress levels, especially in the context of groups of unfamiliar animals. because it may take days to weeks to acclimate to a group environment, enriched individual housing may be preferable when a brief stay is anticipated. however, the benefits of enriched social group housing become evident when stays extend beyond a few weeks. and preserve staff safety, which are especially crucial for newly arrived cats. traditional cages can be modified into condo-style enclosures by creating portals to adjoin two or three smaller cages (figure - ) . regardless of the precise specifications of the enclosures, the importance of the overall quality of the living environment cannot be overemphasized. this includes a holistic approach to husbandry, with careful attention to the way in which cats are handled, noise levels, the provision of creature comforts, positive contact with caregivers, and strict avoidance of overcrowding, as well as good sanitation, medical protocols, and careful monitoring to ensure health and welfare. for long-term housing (e.g., greater than weeks), consideration should also be given to providing space that a b *references , , , , , , , , , , . breeding age should be avoided whenever possible. at a minimum, mature tomcats should be neutered to prevent intermale aggression, urine spraying, and breeding. reproductively intact females may be co-housed with other intact females or with neutered males. in contrast, in breeding colonies, harem-style housing may be used to facilitate breeding (e.g., a few queens with a tomcat). it is also advantageous to house compatible pregnant queens together before delivery, because they will usually share nursing and neonatal care ( figure - ) . after delivery, pairing of queens becomes more difficult. when tomcats are not breeding, they can usually be co-housed with a spayed female, a neutered male, or a compatible juvenile for companionship. other recommended groupings in the context of a breeding colony include postweaning family groups, prepubertal juveniles, or compatible single-sex adults. personality type there are two basic feline personality types: cats that are outgoing, confident, and sociable and those that are relatively timid and shy. cats with bold, friendly temperaments tend to cope and adapt more readily than shy, timid cats. a subset of the bold, friendly personality type is the "assertive" or "bully" cat. bully cats constantly threaten other cats in a group setting in order to control access to food, litter, perches, or the attention of human caregivers. to maintain harmony, removing cats of this personality type from a colony is usually necessary. reassignment is possible, but may prove difficult, necessitating single housing. shy, timid cats sometimes have difficulty interacting successfully with more dominant members of a group or may fall victim to a bully, resulting in chronic stress and increased hiding. placement of shy cats in smaller groups or with calm juvenile cats, where they will not be intimidated or harassed, is generally rewarding and often helps them to "come out of their shells." , similarly, dominant cats will often accept calm, younger cats, as opposed to other adults by whom they may feel threatened. and finally, in the case of some dominant males, the introduction of a female cat will be more likely to be successful. , , the precise space requirements for long-term housing of cats will vary, because it is dependent on many factors (box - ). , of paramount importance is that group size must be small enough to prevent negative interactions among cats and to permit daily monitoring of individuals. cats typically prevent social conflict through avoidance, and adequate space must be available so that cats can maintain social distance as needed. crowding can make it impossible for animals to maintain healthy behavioral distance, creating situations where individuals may not be able to freely access feeding, resting, or elimination space because of social conflicts over colony careful attention to groupings of cats is essential for success. family groups and previously bonded housemates are natural choices for co-housing, , but unfamiliar cats may also be grouped using careful selection criteria. many cats do have preferences for housemates, necessitating conscientious compatibility matching combined with the provision of a high-quality environment. groupings of unfamiliar cats should always be given priority for the largest available enclosures. in addition, cats should always receive appropriate health clearances prior to admission to a group. these should be determined by the specific protocols of the facility; but in most cases, minimum requirements would include that cats be free of signs of contagious disease, tested for felv and fiv, vaccinated against fvrcp, and treated for parasites. in addition to prior relationships, selection criteria for groupings should include age, reproductive status, and personality. age age is an important consideration regarding housing arrangements. to ensure proper social and emotional development, kittens should be housed with their mother at least until they are weaned. because it can be behaviorally beneficial, it is desirable for them to remain with her for a longer period of time when this is feasible. in fact, queens frequently do not fully wean their kittens until to weeks of age if left to their own devices. if older kittens are housed with their mother, it is important to provide a perch that allows her the option of periodically resting away from them if desired. most queens will accept the kittens of another cat; therefore young orphan or singleton kittens should be housed with other lactating queens and/or kittens of similar age/size. in a shelter setting where there is a high turnover of cats, it may be beneficial to house young kittens up to to months of age in large cages or condos for biosecurity purposes. juveniles and adults can be housed in colony rooms or runs but should be segregated by age (e.g., juveniles to months old, young adults, mature adults, geriatrics). well-socialized juveniles tend to adapt quickly in a group setting with other cats of similar ages and exhibit healthy activity and play behavior. in contrast, mature adults and geriatric cats often have little tolerance for the high energy and playful antics of many younger cats, which can cause them substantial stress. for this reason, adult cats should be kept separate from juvenile cats, and aging or geriatric cats separate from other age groups. in animal shelters, compatible cats that enter the shelter together should be housed together regardless of age, whenever possible. unless cats will be used for breeding, group housing of sexually intact cats of all of these reasons, housing cats in small groups is preferred. , , in most instances, the author recommends housing cats in compatible pairs or small groups of not more than three to four individuals. housing cats in runs is ideal for this purpose (figure - ) . a well-equipped, . -× . -m ( -× -ft) run can comfortably house two to three adult cats depending on their familiarity and compatibility, or up to four juveniles (e.g., to months old). juveniles tend to accept a slightly higher housing density than adults. likewise, previously bonded housemates and families will generally peacefully co-exist at a higher density than will unfamiliar cats. when runs are used, they must have a top panel and should be at least . m ( ft) high to allow caregivers easy access for cleaning and care. if chain-link is used, . -cm ( -inch) mesh is ideal, but larger mesh can be used. existing dog kennel runs can be converted into areas for cat housing. this is an important and practical consideration in animal shelters, because many shelters have experienced a decrease in dog intake, while the need for improved cat housing is great. cats and dogs should never be co-housed in the same area; thus conversion should result in an exclusive cat housing area. for colony rooms, the author recommends a minimum enclosure size of approximately to . m × to . m ( to ft × to ft) for colonies of up to a maximum of eight adult cats, or in the case of juveniles, a few more. doubling the size of an enclosure does not necessarily allow a twofold increase in the number of cats that can be properly housed. another author recommends . m ( ft ) per cat as a general guideline for group housing, resources. both crowding and constant introduction of new cats induce stress and must be avoided to ensure proper welfare. the addition of new cats always results in a period of stress for the group, and if there is constant turnover within the group, cats may remain stressed indefinitely. high turnover also increases the risk of infectious disease. if cat group numbers are small, disease exposure will be limited, facilitating control. for • length of stay • overall quality of the environment, including use of vertical space • overall quality of behavioral care • physical and behavioral characteristics of the cat (e.g., age, personality type, prior experience, and socialization) • individual relationships between cats (e.g., family groupings, previously bonded housemates, versus unfamiliar groupings and degree of social compatibility among cats) • turnover of cats (e.g., frequency of introduction of new members) • total room size • absolute number of cats • individual needs and levels of enrichment being used to meet these needs enabling caregivers to better monitor individual appetites and litter box results while allowing cats a period of rest away from one another. alternatively, individual enclosures may only be used for brief periods for meal feedings of canned food, with dry food available free choice in the colony. this sort of arrangement can also be used to facilitate introduction of new cats to the group and represents a desirable option. if design and biosecurity procedures permit, portable intake enclosures could even be transferred to group rooms to smooth the transition of new cats from intake to long-term housing areas. tremendous individual variation exists among cats in the context of social relations with other cats. although introduction of some previously unfamiliar cats will seem effortless and uneventful, introduction of others will result in considerable stress, not only for the new cat but for the entire group as well. for this reason, introductions should always be done under supervision, and whenever possible, they should be gradual. to accomplish this, a new cat can be kept in a separate cage within or adjacent to the group enclosure equipped with food, water, litter, and a hiding box. usually, within a few days, it will be evident by the behaviors of the cats whether or not the new cat can be transferred into the group enclosure without risk of fighting. wellsocialized kittens and juvenile cats frequently adapt readily to group accommodations, and prolonged introductions may not be necessary unless they are shy or undersocialized. in established groups of cats, the introduction or removal of individuals will require a period of adjustment and may result in signs of social stress for members of the colony. these signs usually subside once a new social hierarchy and territorial limits (usually favored resting places) are established. in some cases, arrangement of incompatible cats, even within visible distance of one another, may create substantial anxiety, necessitating rearrangement (figure - ) . in the case of animal shelters, where population interchange is high, it is generally not feasible to maintain consistent groupings of cats. this underscores the absolute necessity of careful selection and compatibility matching, as well as maintaining a variety of housing styles. even in modestly populated, carefully introduced, environmentally enriched colonies, behavior problems may occur. for this reason, some facilities elect to use an "all in-all out" approach to avoid repeated introductions of new cats into stable groups. in animal shelters, bonded pairs and family groupings of cats frequently enter the shelter together and are usually perfect choices for co-housing. because cats do have strong preferences for new roommates, caregivers must expect to find many that are incompatible as roommates. if only one or two cats are responsible for social destabilization of a group, they can acknowledging that many factors influence the spatial needs of cats, including the overall quality of the environment as well as the relationships of the individual animals. in sanctuary and laboratory situations where cats are housed for months to years in stable colonies, larger groupings of cats may be feasible, provided ample space is available. housing arrangements can also be created in which individual enclosures are maintained within a colony room. in this case, cats could be allowed to wander and interact freely in the colony room by day but be confined to their respective enclosures at night, for pair-housing of two adult cats. note the multiple separate areas for resting, perching, hiding, feeding, eliminating, scratching, and playing. b, cats enjoy the increased behavioral options provided by run-style housing. should exceed the number of cats and should be arranged in as many locations within the enclosure as possible. open single perches should be separated by at least . m ( ft) or staggered at different heights to ensure adequate separation, while larger perches should be available for cats who choose to rest together in close proximity. many cats enjoy hammock-style perches or semienclosed box-style perches where they can hide. if there are not enough comfortable, desirable resting and hiding places, cats may choose to lie in litter boxes. comfortable bedding (that is either disposable or can be easily laundered) should be provided. not only do cats demonstrate preferences for resting on soft surfaces, they experience longer periods of normal deep sleep with soft bedding. the environmental temperature should be kept comfortable and constant, and living quarters should be well ventilated, without drafts. by changing location within the colony (e.g., from the cooler surface of the floor to a sunny window), cats should be able to choose the environmental condition they prefer (figure - ) . in colony rooms, installation of stairs, shelves, and walkways are ideal for increasing the use of vertical space (figure - ) . in larger rooms, installation of freestanding towers provides additional living and activity space and contributes to functionally reducing overcrowding (figure - ) . depending on the setting, it may not be desirable for cats to access areas above the level of an arm's reach so that cleaning is easy and cats can be easily retrieved from the highest perches if needed. colony room design should also ensure that cats cannot easily escape. in some cases, constructing a foyer at the entrance to the room will be necessary to minimize the risk of escape when the room is entered (figure - ) . in addition, ceilings should be constructed of solid surfaces, because cats can easily dislodge the usually be reassigned to another colony, because it is often the social grouping, not the individual, that is the problem. if a cat shows persistent incompatibility with other cats, he or she should be housed singly. studies indicate that cats that fight at the time of initial introduction are nearly times more likely to continue fighting in the following weeks and months. if overt fighting occurs, cats should be permanently separated. cohousing of incompatible cats or cats that fight is unacceptable. the success of group housing depends not only on selection of compatible cats and the size of the enclosure but also on the quality of the environment.* a variety of elevated resting perches and hiding boxes should be provided to increase the size and complexity of the enclosure and to separate it into different functional areas, allowing a variety of behavioral choices. the physical environment should include opportunities for hiding, playing, scratching, climbing, resting, feeding, and eliminating. whenever possible, a minimum of litter box and food and water bowl should be provided per to cats and arranged in different locations of the colony space, taking care to separate food and water from litter by at least . m ( ft). in addition, placement should allow cats to access each resource from more than one side, whenever possible, without blocking access to doorways. litter boxes should not be covered, to allow easy access and to prevent entrapment or ambush by other cats. the number of resting boards and perches the importance of a cat-savvy staff that enjoys working with cats cannot be overemphasized. animal care staff must be willing to spend quality time interacting with cats to assure socialization and tractability. , whenever possible, caregivers should be assigned to care for the same cats on a regular basis so that they become aware of the personality of each individual cat, which is necessary for detection of health problems, incompatibilities between cats, and, in the case of breeding colonies, estrous cycling. this is also important, because not all cats uniformly enjoy human companionship and will be more likely to be stressed by the presence of different caregivers, rather than becoming familiar and more at ease with one. in general, regular daily contact and socialization is essential to ensure that cats are docile, easy to work with, and have no fear of humans. caregivers should schedule time each day to interact with "their" cats aside from the activities of feeding and cleaning. some cats may prefer to be petted and handled, while others prefer to interact with caregivers by playing with toys (figure - ) . in particular, human contact is essential for proper socialization of young kittens. a sensitive period of socialization occurs during the development of all infant animals, during which social attachments to members of the same species and other species form easily and rapidly. in kittens, the sensitive period of socialization occurs between and weeks of age, and cats not properly socialized to humans during this time may never permit handling. , beginning shortly after birth, kittens should be handled daily, talked to in a soothing panels typically used for dropped ceilings, and escape into the rafters (figure - ) . in addition to contact with conspecifics, cats must be afforded time for pleasant daily contact with human caregivers. as previously discussed, daily social contact and exercise sessions with humans are especially important for individually caged cats. although social contact is usually highly desirable, it is not invariably pleasant for all cats. personality, socialization, previous experience, and familiarity contribute to whether or not social interactions are perceived as pleasurable, stressful, or somewhere in between. , a b voice, gently petted, and held. interactions should include play (stimulated with toys) as the kittens become ambulatory. for kittens housed in a shelter, socialization must always be balanced with infectious disease control, and caregivers should take precautions accordingly. other forms of stimulation, including those that engage the various senses, are important methods of enriching the living environment by promoting healthy mental and physical activity. for singly housed cats and longterm residents, appropriate levels of additional enrichment should be provided on a daily basis. the provision of birdfeeders, gardens, or other interesting stimuli in the external environment can enhance the internal environment of the colony. resting perches in view of windows or other pleasant areas of the facility are especially desirable. other novel and enriching visual stimuli include cat-proof aquariums with fish, water fountains, bubbles, perpetual motion devices, and videos especially designed for cats (figures - to . a radio playing soft, low music in the room provides a welcome distraction and important source of play items that stimulate prey drive and physical activity, such as plastic balls, rings, hanging ropes, springmounted toys, plastic wands, and catnip toys, should also be provided but must be either sanitizable or disposable. empty cardboard boxes and paper bags are inexpensive, disposable, and stimulate exploration and play behavior as well as scratching. cats tend to be most stimulated by active toys, including wiggling ropes, wands with feathers, kitty fishing poles, and toys that can be slid or rolled to chase. many cats enjoy chasing stimulation. in addition, it may help to habituate cats to human voices and prevent them from being startled by loud noises. most caregivers also enjoy listening to the radio, and happy caregivers create a relaxed environment. the provision of scratching boards is especially important, and a variety of sturdy surfaces, both horizontal and vertical, should be provided for scratching. sisal rope, the backs of carpet squares, and corrugated cardboard are all useful (figure - ) . many cats like to smell and chew grass, and containers of cat grass or catnip can be introduced for brief periods to stimulate activity (figure - ) . providing novel sources of food is another important source of stimulation and can be easily accomplished by hiding food in commercially available food-puzzle toys or in cardboard boxes or similar items with holes such that the cat has to work to extract pieces of food ( figure - ) . , positive reinforcement-based training obedience training using clickers with food rewards is an excellent form of enrichment, combining social contact with caregivers together with both mental and physical stimulation. positive reinforcement training using a target stick is a powerful tool for teaching shy cats to approach the front of an enclosure. teaching cats awaiting adoption to perform tricks is not only stimulating for them, but it often makes them more attractive to potential adopters (figure - ) . a cardboard tube, and a plastic container with holes). treats are hidden inside, and they will have to work to extract pieces of food. novel feeding is an excellent source of enrichment for cats that are housed long term. (e.g., feeding, cleaning, enrichment activities), and unpredictable caregiving has been shown to dramatically increase stress. if events that are perceived as stressful (such as cleaning time) occur on a predictable schedule, cats learn that a predictable period of calm and comfort will always occur in between. cats also respond to positive experiences in their daily routines. for example, feeding and playtime may be greatly anticipated; thus scheduling positive daily events (e.g., a treat at : pm every day) should also be a priority. erratic periods of light and darkness are also known to be significant sources of stress for cats. animals possess natural circadian rhythms and irregular or continuous patterns of light or darkness are inherently stressful. lighting should be maintained on a regular the beams of laser pointers, small flashlights, or suspended rotating disco balls. commercially available electronic toys that stimulate play are especially useful in long-term settings (figure - ) . varied toys should be substituted regularly to ensure continued interest. in some climates, cats may be housed comfortably in outdoor enclosures where fresh air, sunshine, and other stimuli can help to create a healthy environment ( figures - and - ) . , , when indoor group enclosures connect to outdoor enclosures, it is important to have ample space for passage between them (e.g., more than one doorway) so that cats can pass freely. cats will also benefit greatly from consistent daily routines of care. they become entrained to schedules of care adoption, or euthanasia (when no other options exist) may be necessary to ensure cat welfare. achieving population wellness requires a healthy environment. thus the clinician's final task in creating a population wellness program is to develop tailored schedule, with lights on by day and off by night. whenever possible, full-spectrum and/or natural lighting is ideal. housed cats require active daily monitoring by staff trained to recognize signs of stress and social conflict. to the inexperienced observer, such signs may appear subtle (figure - ) . it is often the absence of normal behaviors (such as engaging in grooming or exercise) or subtle social signals (such as covert guarding of resources or dominant staring) that signify problems. careful observers will note these behaviors and respond accordingly to ensure that stress or conflicts do not persist. when cats are well adjusted and housing arrangements meet their behavioral needs, they display a wide variety of normal behaviors, including a good appetite and activity level, sociability, grooming, appropriate play behavior, and restful sleeping (figure - ) . , ultimately, the success of adaptation of cats to a new environment will depend on both the quality of the environment and the adaptive capacity of the individual. although most adapt to new environments with time, some never adjust and remain stressed indefinitely, ultimately resulting in decline of physical as well as emotional health. when cats fail to adjust to their environment and remain markedly stressed and fearful despite appropriate behavioral care, every effort must be made to prevent long-term stays. depending on the circumstances, transfer to another colony room, foster care, a shelter will result in saving more lives. to the contrary, euthanasia rates are highly correlated to intake rates, regardless of the number of animals that a facility houses. in many instances, keeping more animals in the shelter may actually reduce the organization's ability to help animals, because time and resources are tied up caring for a crowded, stressed population, rather than focusing on adoption or other positive outcomes. in shelter medicine, the term population management is used to refer to an active process of planning, ongoing daily evaluation, and responding to changing conditions as an organization cares for multiple animals. , the major goal of population management is to minimize the amount of time any individual animal spends confined in the shelter, while maximizing the organization's lifesaving capacity. moving animals through the system efficiently is the foundation of effective population management. to move animals through the shelter more quickly, delays in decision making and the completion of procedures (e.g., intake processing, transfer from holding to adoption areas, spay/neuter surgery) must be eliminated or minimized whenever possible. in openadmission shelters, even delays of to days can have a dramatic effect on the shelter's daily census, particularly for shelters handling thousands of animals per year. this, in turn, affects the ability to provide adequate care. it is important to recognize that effective population management does not change the final disposition of an animal. it does mean that determinations are made as soon as possible, which serves both the individual animal as well as the population as a whole. for wellness programs to be effective, a clean and sanitary environment must be maintained. not only does this promote cat and human health, but it also promotes staff pride as well as public support. in addition to protocols for routine daily cleaning and disinfection procedures, protocols should be in place for periodic deep cleaning and disinfection as well as procedures to be used in the event of disease outbreaks. when crafting protocols, it is important to recognize that cleaning and disinfection are two separate processes. the cleaning process involves the removal of gross wastes and organic debris (including nonvisible films) through the use of detergents, degreasers, and physical action. although this process should result in a visibly clean surface, it does not necessarily remove all of the potentially harmful infectious agents that may be present. disinfection is the process that will destroy most of these agents, but it cannot be accomplished until surfaces have been adequately cleaned. disinfection is usually accomplished through the application of chemical compounds or disinfectants. the most commonly used of these are reviewed in protocols focused on optimizing environmental conditions that favor cat health. once again, all essential elements as noted should be addressed. perhaps the most critical aspect of environmental management is to ensure a modest population density. high population density increases opportunities for introduction of infectious disease while increasing the contact rate among members of a group. both the number of asymptomatic carriers of disease, such as those with upper respiratory infection, as well as susceptible cats in a given group are likely to increase, enhancing the odds of disease transmission among group members through both direct contact as well as fomites. in addition, crowding also increases the magnitude of many environmental stressors (e.g., noise levels, air contaminants) and compromises animal husbandry, all of which induce unnecessary stress and further inflate the risk of disease in the population. indeed, crowding is one of the most potent stressors recognized in housed animals. although adequate space for animals is essential, it is crucial to recognize that crowding is not solely dependent on the amount of available space. it is also a function of the organization's ability to provide proper care that maintains animal health and well-being. every organization has a limit to the number of animals for which it can provide proper care. when more animals are housed than can be properly cared for within the organization's capacity, caregivers become overwhelmed, and animal care is further compromised. , , in animal shelters, crowding may also negatively impact adoption rates, because potential adopters often find crowded environments to be overwhelming and uninviting. if disease spread results as a consequence of the environmental conditions, animal adoptions may be further disrupted. although unexpected shelter intake may occasionally result in temporary crowding, a good wellness program dictates that protocols must be in place to alleviate crowding and maintain a modestly populated environment for the health and protection of the animals and staff. regardless of the setting, facilities must limit the number of animals housed to the number for which they can provide proper space and care. there are three basic methods of reducing crowding: ( ) limiting the admission (or births) of new animals into a population, ( ) increasing release of animals from a population, and ( ) euthanasia. in animal shelters, management practices that minimize each animal's length of stay and programs that speed or increase adoption, owner reunification, or transfer (e.g., to rescue or foster care) help to minimize crowding and maximize the number of animals that an organization can serve. it is a common misperception that housing more animals in • although commonly used, they must be applied to clean hands and allowed seconds of contact time to be effective. • they are highly effective against bacteria, but have only moderate activity against viral agents, including feline calicivirus (fcv). • they should not be used as a substitute for hand washing or the use of gloves. • chlorhexidine is the most commonly used biguanide and is relatively expensive. its major use is as a surgical preparation agent. • although biguanide compounds have broad antibacterial activity, they have limited efficacy against viruses and are ineffective against nonenveloped viruses, such as panleukopenia and fcv. therefore they are not recommended as general-purpose environmental disinfectants. • household bleach ( . % sodium hypochlorite) is the most commonly used chlorine compound and is an excellent, safe, and highly cost-effective disinfectant when used correctly. • at a dilution of : , bleach is highly effective against bacteria and viruses, including nonenveloped viruses, such as panleukopenia and fcv. • solutions must be made fresh daily and stored in opaque containers, because bleach is highly unstable once mixed with water and degrades in the presence of ultraviolet light. • surfaces must be thoroughly cleaned with a detergent, rinsed, and dried prior to the application of bleach, because it is ineffective in the presence of detergents and organic material. • proper disinfection requires minutes of contact time with a bleach solution. • although bleach is not effective when mixed with detergents, it can be safely and effectively mixed with quaternary ammonium compounds, which do provide some cleaning activity. therefore this combination can be used for cleaning and disinfection, provided gross organic material is first removed and adequate contact time is allowed. the addition of bleach improves the disinfection properties of the solution, making it effective against nonenveloped viruses, including panleukopenia and fcv. • concentrations stronger than a : dilution can result in respiratory irritation for both animals and people, as well as increased facility corrosion, and are therefore not recommended for routine use. • at a dilution of : , bleach will destroy dermatophyte spores. however, cats must be removed from the environment prior to application of this concentration. • the use of calcium hypochlorite (wysiwash, st. cloud, fla.) is becoming more common and offers the potential advantages of reduced contact time and a neutral ph, which prevents corrosion. oxidizing agents quarantine involves the holding of healthy-appearing animals. it is most useful when animals enter a closed population to ensure that they are not incubating disease when they are introduced into the general population. quarantine areas, with rigid biosecurity procedures in place, should be used to segregate healthy animals for observation. the use of such areas not only allows apparently healthy animals to be observed for developing signs of infectious disease, but it also allows time for response to vaccination in a highly biosecure environment where exposure risks are minimized. the use of quarantine is a mainstay of effective infectious disease control programs and is intended to prevent the introduction of disease into a population. it should be used whenever it is feasible to implement effectively, such as in a laboratory setting, a private cattery, or a low-volume, limited-admission sanctuary setting. however, quarantine practices are not effective in most animal shelters, because the high volume and turnover of animals precludes proper implementation of a true quarantine where an "all in-all out" system is used. instead, incoming animals are usually added to the "quarantine group" on a daily basis, effectively defeating the purpose of true quarantine and simply prolonging the animal's stay. this is especially concerning given the fact that a cat's length of stay in a shelter is a major risk factor for development of upper respiratory infection. for this reason, the use of quarantine is not recommended in most shelter settings. instead, high biosecurity areas are recommended for housing the most susceptible animals (e.g., kittens less than to months of age). on the other hand, quarantine is warranted when a serious disease is discovered in a shelter population. if healthyappearing animals are exposed during a serious outbreak, quarantine procedures should be used to stop the movement of animals and prevent further spread of disease. if possible, temporary closure to admittance is also recommended. quarantine may also be required in bite cases to ensure compliance with state rabies laws. the particular population setting will guide the clinician's determination regarding implementation and length of quarantine, if any. a -day quarantine is sufficient to determine that cats are not incubating many common infectious diseases, including feline panleukopenia. however, other diseases, including feline leukemia virus and dermatophytosis, can have longer incubation periods and will therefore require a longer quarantine period. , in breeding colonies, early weaning and quarantine have been advocated to prevent infection of kittens with feline coronavirus. pregnant queens are isolated, and product selection should take into consideration the conditions present in a given environment (e.g., the type of surface and the presence of organic matter) and the compound's activity against the pathogens for which the animals are at greatest risk. the nonenveloped viruses, panleukopenia and feline calicivirus, are of particular concern. it is important to note that despite product label claims to the contrary, multiple independent studies have consistently shown that quaternary ammonium disinfectants do not reliably inactivate these important feline pathogens. , , in addition to selecting effective agents, ensuring adequate contact time followed by thorough drying of surfaces is essential for achieving proper disinfection. protocols should include detailed methods for achieving both cleaning and disinfection. when performed properly and regularly, these practices decrease both the dose and duration of exposure to infectious agents. box - outlines essential considerations for the development of cleaning and disinfection protocols. segregation refers to the separation of animals from the main group or into subpopulations as necessary to promote health. segregation of cats by physical and behavioral health status is essential for infectious disease control, stress reduction, and safety. in animal shelters, segregation may also be required to ensure compliance with animal control procedures as prescribed by state or local ordinances. depending on the setting, consideration should be given to separating cats by gender and reproductive status (e.g., intact, neutered, in heat, pregnant, nursing), physical and behavioral health status (e.g., apparently healthy, signs of contagious disease, reactive, feral), and life stage. a variety of separate areas will be necessary, depending on the needs of the given population and the context of the setting. the wellness program should define these areas in order to optimize cat health, while providing for the necessary functions of the facility. depending on the setting, consideration should be given to establishing areas for quarantine, isolation, general holding, adoption, and long-term housing, as well as to tailoring these by life stage. for example, the very young and very old typically require more specialized care than healthy juveniles and adults. kittens less than to months of age are particularly susceptible to infectious disease, and extra care must be taken to heighten biosecurity and limit their exposure. in particular, geriatric cats require comfortable, quiet quarters with careful attention to stress reduction (e.g., the provision of a secure hiding place and a dedicated caregiver to enhance bonding and comfort). if cats are used for breeding, functional areas will be required to facilitate mating, queening, and kitten care. and, as previously • staff must wear personal protective equipment, as necessary, to prevent exposure to chemicals and/or pathogens. • thorough cleaning and disinfection of enclosures should occur between occupants and as part of periodic deep cleaning procedures. • cats must be removed from enclosures during these procedures. • "spot cleaning" is generally sufficient for apparently healthy cats that will continue to occupy the same enclosure. • the cat remains in the enclosure while it is cleaned and soiled material is removed. • this method is often less stressful for cats (see figure - ). • separate staff should clean and care for animals in areas with highly susceptible or sick animals, whenever possible. • at minimum, attention should be given to the order of cleaning. • the least contaminated areas should be cleaned before those that are the most contaminated. kittens are weaned as early as possible (e.g., to weeks of age) and placed in strict quarantine. in this manner, as maternal antibody wanes and kittens become susceptible to the virus, exposure and infection are prevented. however, it is important to note that the level of biosecurity required for success is difficult to achieve. furthermore, eventual exposure and infection are highly likely because of the ubiquitous nature of coronaviruses. in addition, because of the importance of the mother-kitten relationship to normal social and emotional development, this management practice may not always be desirable. healthy environmental conditions in isolation areas promote recovery, and their importance cannot be overemphasized. crowding, noise, and stress must be avoided, and facilities must be easy to clean and disinfect. room temperature should be warm and comfortable with good air quality. windows are ideal, because natural sunlight is always beneficial to animal health and healing. strict biosecurity in quarantine and isolation areas, with attention to traffic patterns and the use of protective clothing, such as gowns and shoe covers, is essential. footbaths are insufficient to prevent transfer of infectious agents on shoes. this is because disinfectants typically require minutes of contact time and may be poorly effective in the presence of organic debris. in fact, footbaths may even contribute to the spread of disease. dedicated boots or shoe covers should be used when entering contaminated areas. , in addition, separate, designated staff should care for animals in high biosecurity areas whenever possible. by design, traffic patterns should move from the healthiest and most susceptible groupings to the least susceptible, and finally to isolation areas housing sick animals. observation windows and signage are useful to reduce traffic flow into high-risk areas. staff hygiene is extremely important, and the importance of diligent hand washing cannot be overemphasized. where space or facilities are not available, foster care may represent a viable and medically sound option for quarantine or isolation in some settings. for instance, in animal shelters, foster care is particularly useful for the care of preweaning-age kittens. foster homes must be monitored to ensure that cats receive proper care and that resident animals are protected from disease exposure. in addition to ensuring proper population density, segregation, and sanitation procedures, there are several other essential aspects of facility operations that must be incorporated into a population wellness program. these include heating, ventilation, and air conditioning (hvac) considerations, noise and pest control, general facility maintenance, and staff training. extremes or fluctuations in temperature and humidity, as well as poor ventilation and air quality, can compromise animal health. poor ventilation and high humidity favor the accumulation of infectious agents, while dust and fumes may be irritating to the respiratory tract. many cats are particularly sensitive to drafts and chilling, both of which can predispose to upper respiratory general holding, housing, adoption, and other areas in many settings, general holding areas are used for housing healthy juvenile and adult cats at intake. in animal shelters, it is important to consider that length of stay is associated with an increased risk of feline upper respiratory disease and that vaccination against core diseases often rapidly confers immunity. for these reasons, holding periods should be minimized whenever possible. in some cases, holding times will be influenced by legally required holding periods prescribed by state laws that allow owners a chance to reclaim lost pets. legal holding periods are usually not required for owner-relinquished pets and preweaning-age animals, but a brief medical hold (e.g., to days) for evaluation and triage is usually warranted. regardless, management practices that reduce length of stay are generally best for population health in a shelter setting. immunity is often strengthened with time through a combination of both active and passive immunity resulting from vaccination and exposure. upper respiratory disease is often endemic in cat populations, and in open populations, constant introduction of large numbers of carriers and susceptible cats make exposure likely. as length of stay increases, many cats develop and recover from respiratory disease. as animals acclimate to their environment and gain immunity, less stringent biosecurity requirements may be required for long-term housing areas, depending on the particular setting. in animal shelters, the public is usually allowed to interact with cats in adoption areas, which is another management consideration. isolation areas are used to segregate sick animals from the general population. immediate isolation of animals with signs of infectious disease is critical to effective control. isolation should be targeted by age and disease. for example, separate isolation areas should be available for cats and kittens with respiratory disease and those with gastrointestinal disease, whenever possible. in populations where upper respiratory infection is problematic, having two isolation areas for cats with respiratory infections is ideal: one area for those cats with moderate to severe signs that will require more intensive monitoring and treatment, and a separate area for those cats with only mild clinical signs and those that have been treated and are nearly recovered. when mildly symptomatic cats can be housed separately from those that are very ill, staff compliance with isolation procedures are often improved. cats with non-infectious conditions should also be housed in separate areas for treatment, and, in some cases, housing in the general population is appropriate. prevents exchange of air among them and is recommended, because air pressure gradients that recirculate or cause exchange of air between rooms have been associated with the spread of disease by aerosols. when applying these standard recommendations to a particular setting, there are some practical considerations that should be taken into account. first, even when ventilation systems provide to room air changes per hour, airflow may be restricted inside of cages or other enclosures within the room. in other words, the body of the room may be well ventilated, yet inside the cages, the air may remain relatively stagnant. in this case, ventilation may be improved by altering the housing design or arrangement; for example, the use of flow-through cages, runs, free-range rooms, or outdoor access may result in improved air quality. when considering the recommendations for % fresh, nonrecycled air with separate ventilation systems in various areas of the facility, consideration should be given to the fact that respiratory pathogens in cats are not aerosolized because of the cats' small tidal volume. although droplet transmission is possible, droplet spray does not extend more than feet, and most transmission of respiratory disease in cats is through direct contact with infected cats, carriers, or fomites. although this recommendation seems prudent to consider, especially for isolation areas, it is very expensive to install and operate this type of ventilation system throughout a facility, especially in very cold or very hot climates. if air quality remains good and the facility maintains effective comprehensive wellness protocols, it may not be necessary for animal health. more research is needed on the impact of such air exchange, but in the meantime, the author recommends consulting with an hvac specialist to establish effective and efficient settings to suit the specific needs of the given population. in addition to ensuring good ventilation, it is imperative to use other strategies for maintaining good air quality, including regular maintenance of filters, control of dust and dander through routine vacuuming and periodic deep cleaning, and the use of dust-free litter. noise control is another important consideration. it is crucial to keep cats out of auditory range of dogs, because many are profoundly stressed by the sounds of barking. also, staff should be trained to reduce or avoid other sources of noise whenever possible. the installation of sound-proofing systems may be necessary for noise abatement and stress reduction. routine pest control may also be required, depending on the setting. it may be necessary to treat the environment for fleas, ticks, or other insects or ectoparasites. products used to treat the environment must be selected carefully, because cats are extremely sensitive to the toxic effects of many insecticides. in many instances, it will infection. heating, ventilation, and air conditioning (hvac) specialists are uniquely qualified to help establish and maintain the environmental conditions required for animal health. when facilities are designed specifically for housing animals, these specialists should be consulted beforehand to ensure installation of the most effective and efficient systems possible. in reality, many facilities that house cats, including private catteries and shelters, among others, were not originally built for this purpose. retrofitting existing facilities with the ideal hvac system is often neither logistically nor financially feasible. regardless, consultation with hvac specialists is recommended in order to maximize the potential of the facility's existing system. the recommended temperature range for cats is between ° c and ° c ( ° f and ° f) with a temperature setting in the low-to mid- s celsius ( s fahrenheit) being typical. the temperature setting should be determined according to the specific animals' needs. for example, neonatal kittens are more susceptible to hypothermia and generally require warmer temperatures than healthy adult cats. the location of the cats may also be a consideration. for example, enclosures located closer to floor level are often a few degrees cooler than those at higher levels. the exact temperature setting may also vary somewhat based on the season of the year. for instance, power companies typically recommend keeping the temperature between ° c and ° c ( ° f and ° f) during hot weather to conserve electricity and reduce power bills. laboratory guidelines recommend % to % humidity for cats. higher humidity (e.g., %) may be advantageous in areas housing cats with respiratory disease because moist air may be beneficial to the respiratory passages, whereas lower humidity (e.g., % to %) may be beneficial in other areas in order to reduce survival of infectious agents in the environment. although the range considered acceptable is large, a given room should have a relatively constant humidity (i.e., it should not have large fluctuations). hosing or even mopping a room usually results in temporary spikes in humidity, but these will be short lived in a well-ventilated room. adequate ventilation is crucial for good air quality. this is especially important for cats, because good air quality is essential for control of upper respiratory disease. ten to fifteen air changes per hour is the standard recommendation for an animal room, but more or less airflow may be acceptable or necessary depending on the housing density. theoretically, the best case scenario, and what is typical in laboratory animal settings, is for the hvac system to allow for % fresh (e.g., nonrecycled) air in each room so that the air entering a given room is exhausted out of the building and not recirculated to another room. maintaining separate ventilation systems for various rooms or areas of a facility ensure both the physical and behavioral health of cats, as well as a healthy environment. a proactive, holistic approach coupled with compassion is required. when these are combined with careful attention to the unique needs and stress responses of cats, the result will be "healthy, happy cats." be necessary to remove cats during their application and only return them to the environment once it is thoroughly dried and ventilated. if rodent control is necessary, the use of rodenticide baits should be avoided, because cats can be exposed even if the bait is not within their reach. rodents that have ingested the poisonous bait may enter an animal enclosure and, if the animal ingests the rodent, the poison will affect that animal. humane live traps can be used to capture rodents for removal from a facility. food containers should be kept tightly sealed, and clutter should be minimized to discourage pests in the environment. general building maintenance procedures (e.g., regular inspection and servicing with repairs as needed) are also important considerations for the maintenance of a healthy environment. for example, periodic resealing of floors may be required as well as maintenance of plumbing fixtures to repair leaks or other problems. developing and following written standard operating procedures and daily, weekly, monthly, and quarterly checklists will ensure that systematic schedules of maintenance are carried out in a timely fashion. regular staff training is essential for implementing effective population wellness programs. simply stated, staff caring for animals must be qualified to do so. to a large extent, their knowledge and skill will determine the success or failure of the wellness program. embracing a culture of training promotes high-quality animal care as well as human safety. both formal and on-thejob training should be provided to ensure that a staff has the knowledge and skills required to perform their assigned tasks. protocols should be established for all levels of training, and a system should be in place to ensure proficiency. staff training should be documented, and continuing education should be provided to maintain and improve skills. finally, training must include the provision of information about zoonoses and other occupational health and safety considerations. regardless of the setting, maintaining population health is essential for animal welfare as well as to meet the goals of the particular population. population health depends on implementation of comprehensive wellness protocols, systematic surveillance, and excellent management. facilities must establish goals for animal health, and wellness protocols must be regularly evaluated and revised to ensure that these goals are met. the bulk of efforts must focus on preventive strategies to control of feline coronavirus in breeding catteries by serotesting, isolation, and early weaning guidelines for the diagnosis, treatment and prevention of heartworm (dirofilaria immitis) infection in cats american society for the prevention of cruelty to animals (aspca): mission possible, comfy cats. shelter temperament evaluations for cats microchipping of animals association of shelter veterinarians (asv): board position statement on cats who test positive for felv and fiv association of shelter veterinarians (asv): board position statement on veterinary supervision in animal shelters association of shelter veterinarians (asv): standards of care for animal shelters gender differences in the social behavior of the neutered indoor-only domestic cat beaver bv: fractious cats and feline aggression a game of cat and house: spatial patterns and behavior of domestic cats (felis catus) in the home affiliative behaviours of related and unrelated pairs of cats in catteries: a preliminary report immunisation against panleukopenia: early development of immunity cvma): a code of practice for canadian cattery operations behavioral and physiological correlates of stress in laboratory cats the cat: its behavior, nutrition and health cfa cattery standard minimum requirements feline heartworm (dirofilaria immitis) infection: a statistical elaboration of the duration of the infection and life expectancy in asymptomatic cats environmental factors in infectious disease immunoprophylaxis and immunotherapy infectious disease management in animal shelters scaredy cat or feral cat? animal sheltering the lowdown on upper respiratory infections in cats in griffin b: a model of non-invasive monitoring of feline ovarian function in the domestic cat domestic cats as laboratory animals recognition and management of stress in housed cats stress and immunity: a unifying concept effects of a synthetic facial pheromone on behavior of cats small animal clinical nutrition housing design and husbandry management to minimize transmission of disease in multi-cat facilities implementing a population health plan in an animal shelter: goal setting, data collection and monitoring, and policy development feline infectious disease control in shelters commission on life sciences, national research council: guide for care and use of laboratory animals questions and answers on the effects of surgically neutering dogs and cats virucidal efficacy of the newer quaternary ammonium compounds stress and adaptation of cats (felis silvestris catus) housed singly, in pairs, and in groups in boarding catteries effects of density and cage size on stress in domestic cats (felis silvestris catus) housed in animal shelters and boarding catteries socialization and stress in cats (felis silvestris catus) housed singly and in groups in animal shelters centers for disease control: healthy pets, healthy people responses of cats to nasal vaccination with a live, modified feline herpesvirus type use of fipronil to treat ear mites in cats counsel of europe: guidelines for accommodation and care of animals. proposed revision to appendix a to the european convention for the protection of vertebrate animals used for experimental and other scientific purposes. minimum cage floor area for cats soft surfaces: a factor in feline psychological well-being social organization in the cat: a modern understanding social behavior and aggressive problems of cats descriptive epidemiology of feline upper respiratory tract disease in an animal shelter sanitation and disinfection all together now: group-housing cats behavioral differences between owner surrender and stray domestic cats after entering an animal shelter a clinical trial of intranasal and subcutaneous vaccines to prevent upper respiratory infection in cats at an animal shelter virucidal efficacy of four new disinfectants influence of visual stimulation on the behaviour of cats housed in a rescue shelter feline dental prophylaxis and homecare disinfection efficacy against parvoviruses compared with reference viruses farm animal welfare council: five freedoms feline respiratory disease experimental induction of feline viral rhinotracheitis in fvr-recovered cats evaluation of the efficacy of disinfectant footbaths as used in veterinary hospitals national council on pet population study and policy: the shelter statistics survey animal welfare advisory committee: companion cats code of welfare five key population management factors affecting shelter animal health cat housing in rescue shelters: a welfare comparison between communal and discrete-unit housing recognizing and managing problem behavior in breeding catteries quality of life in long-term confinement maddie's infection control manual for animal shelters a review of feline infectious peritonitis virus observations on the epidemiology and control of viral respiratory disease in cats employee reactions and adjustment to euthanasia related work: identifying turning points through retrospective narratives the aafp feline vaccine advisory panel report welfare of cats in a quarantine cattery recommendations for the housing of cats in the home, in catteries and animal shelters, in laboratories and in veterinary surgeries comfortable environmentally enriched housing for domestic cats efficacy of fipronil in the treatment of feline cheyletiellosis virucidal disinfectants and feline viruses the influence of food presentation on the behavior of small cats in confined environments validation of a temperament test for domestic cats evaluation of the effects of footwear hygiene protocols on nonspecific bacterial contamination of floor surfaces in an equine hospital the human-cat relationship editor: cattery design: the essential guide to creating your perfect cattery intercat aggression in households following the introduction of a new cat feline leukemia virus and feline immunodeficiency virus american association of feline practitioners feline retrovirus management guidelines intercat aggression: a retrospective study examining types of aggression, sexes of fighting pairs and effectiveness of treatment evaluation of collars and microchips for visual and permanent identification of pet cats characterization of animal with microchips entering shelters in vitro sensitivity of commercial scanners to microchips of various frequencies sensitivity of commercial scanners to microchips of various frequencies implanted in dogs and cats search and identification methods that owners use to find a lost cat provision of environmentally enriched housing for cats environmentally enriched housing for cats when singly housed managing oral health in breeding catteries assessment of stress levels among cats in four shelters enriching the environment of the laboratory cat the impact of paternity and early socialisation on the development of cats' behaviour to people and novel objects quality of life in animals development of a mental wellness program for animals toxicology brief: the most common toxicoses in cats the domestic cat. perspective on the nature and diversity of cats definition of wellness behavioral effects of cage enrichment in single-caged adult cats treatment of dermatophytosis in dogs and cats: review of published studies development of an in vitro, isolated, infected spore testing model for disinfectant testing of microsporum canis isolates quality-of-life assessment in pet dogs aafp-aaha. feline life stage guidelines meet your match and feline-ality adoption program key: cord- - brd efp authors: friston, karl j.; parr, thomas; zeidman, peter; razi, adeel; flandin, guillaume; daunizeau, jean; hulme, ollie j.; billig, alexander j.; litvak, vladimir; moran, rosalyn j.; price, cathy j.; lambert, christian title: dynamic causal modelling of covid- date: - - journal: wellcome open res doi: . /wellcomeopenres. . sha: doc_id: cord_uid: brd efp this technical report describes a dynamic causal model of the spread of coronavirus through a population. the model is based upon ensemble or population dynamics that generate outcomes, like new cases and deaths over time. the purpose of this model is to quantify the uncertainty that attends predictions of relevant outcomes. by assuming suitable conditional dependencies, one can model the effects of interventions (e.g., social distancing) and differences among populations (e.g., herd immunity) to predict what might happen in different circumstances. technically, this model leverages state-of-the-art variational (bayesian) model inversion and comparison procedures, originally developed to characterise the responses of neuronal ensembles to perturbations. here, this modelling is applied to epidemiological populations—to illustrate the kind of inferences that are supported and how the model per se can be optimised given timeseries data. although the purpose of this paper is to describe a modelling protocol, the results illustrate some interesting perspectives on the current pandemic; for example, the nonlinear effects of herd immunity that speak to a self-organised mitigation process. the purpose of this paper is to show how dynamic causal modelling can be used to make predictions-and test hypotheses-about the ongoing coronavirus pandemic (huang et al., ; wu et al., ; zhu et al., ) . it should be read as a technical report , written for people who want to understand what this kind of modelling has to offer (or just build an intuition about modelling pandemics). it contains a sufficient level of technical detail to implement the model using matlab (or its open source version octave), while explaining things heuristically for non-technical readers. the examples in this report are used to showcase the procedures and subsequent inferences that can be drawn. having said this, there are some quantitative results that will be of general interest. these results are entirely conditional upon the model used. dynamic causal modelling (dcm) refers to the characterisation of coupled dynamical systems in terms of how observable data are generated by unobserved (i.e., latent or hidden) causes (friston et al., ; moran et al., ) . dynamic causal modelling subsumes state estimation and system identification under one bayesian procedure, to provide probability densities over unknown latent states (i.e., state estimation) and model parameters (i.e., system identification), respectively. its focus is on estimating the uncertainty about these estimates to quantify the evidence for competing models, and the confidence in various predictions. in this sense, dcm combines data assimilation and uncertainty quantification within the same optimisation process. specifically, the posterior densities (i.e., bayesian beliefs) over states and parameters-and the precision of random fluctuations-are optimised by maximising a variational bound on the model's marginal likelihood, also known as model evidence. this bound is known as variational free energy or the evidence lower bound (elbo) in machine learning (friston et al., ; hinton & zemel, ; mackay, ; winn & bishop, ) . intuitively, this means one is trying to optimise probabilistic beliefs-about the unknown quantities generating some data-such that the (marginal) likelihood of those data is as large as possible. the marginal likelihood or model evidence can always be expressed as accuracy minus complexity. this means that the best models provide an accurate account of some data as simply as possible. therefore, the model with the highest evidence is not necessarily a description of the process generating data: rather, it is the simplest description that provides an accurate account of those data. in short, it is 'as if' the data were generated by this kind of model. importantly, models with the highest evidence will generalise to new data and preclude overfitting, or overconfident predictions about outcomes that have yet to be measured. in light of this, it is imperative to select the parameters or models that maximise model evidence or variational free energy (as opposed to goodness of fit or accuracy). however, this requires the estimation of the uncertainty about model parameters and states, which is necessary to evaluate the (marginal) likelihood of the data at hand. this is why estimating uncertainty is crucial. being able to score a model-in terms of its evidence-means that one can compare different models of the same data. this is known as bayesian model comparison and plays an important role when testing different models or hypotheses about how the data are caused. we will see examples of this later. this aspect of dynamic causal modelling means that one does not have to commit to a particular form (i.e., parameterisation) of a model. rather, one can explore a repertoire of plausible models and let the data decide which is the most apt. dynamic causal models are generative models that generate consequences (i.e., data) from causes (i.e., hidden states and parameters). the form of these models can vary depending upon the kind of system at hand. here, we use a ubiquitous form of model; namely, a mean field approximation to loosely coupled ensembles or populations. in the neurosciences, this kind of model is applied to populations of neurons that respond to experimental stimulation (marreiros et al., ; moran et al., ) . here, we use the same mathematical approach to model a population of individuals and their response to an epidemic. the key idea behind these (mean field) models is that the constituents of the ensemble are exchangeable; in the sense that sampling people from the population at random will give the same average as following one person over a long period of time. under this assumption , one can then work out, analytically, how the probability distribution over various states of people evolve over time, e.g., whether someone was infected or not. this involves parameterising the probability that people will transition from one state to another. by assuming the population is large, one can work out the likelihood of observing a certain number of people who were infected, given the probabilistic state of the population at that point in time. in turn, one can work out the probability of a sequence or timeseries of new cases. this is the kind of generative model used here, where the latent states were chosen to generate the data that are-or could be-used to track a pandemic. figure provides an overview of this model. in terms of epidemiological models, this can be regarded as an extended seir (susceptible, exposed, infected and recovered) compartmental model (kermack et al., ) . please see (kucharski et al., ) for an application of this kind of model to covid- . there are number of advantages to using a model of this sort. first, it means that one can include every variable that 'matters', such that one is not just modelling the spread of an infection but an ensemble response in terms of behaviour (e.g., social distancing). this means that one can test hypotheses about the contribution of various responses that are installed in the model-or what would happen under a different kind of response. a second advantage of having a generative model is that one can evaluate its evidence in relation to alternative models, and therefore optimise the structure of the model itself. for example, does social distancing behaviour depend upon the number of people who are infected? or, does it depend on how many people have tested positive for covid- ? (this question is addressed below). a third advantage is more practical, in terms of data analysis: because we are dealing with ensemble dynamics, there is no need to create multiple realisations or random samples to estimate uncertainty. this is because the latent states are not the states of an individual but the sufficient statistics of a probability distribution over individual states. in other words, we replace random fluctuations in hidden states with hidden states that parameterise random fluctuations. the practical consequence of this is that one can fit these models quickly and efficiently-and perform model comparisons over thousands of models. a fourth advantage is that, given a set of transition probabilities, the ensemble dynamics are specified completely. this has the simple but important consequence that the only unknowns in the model are the parameters of these transition probabilities. crucially, in this model, these do not change with time. this means that we can convert what would have been a very complicated, nonlinear state space model for data assimilation into a nonlinear mapping from some unknown (probability transition) parameters to a sequence of observations. we can therefore make precise predictions about the long-term future, under particular circumstances. this follows because the only uncertainty about outcomes inherits from the uncertainty about the parameters, which do not change with time. these points may sound subtle; however, the worked examples below have been chosen to illustrate these properties. this technical report comprises four sections. the first details the generative model, with a focus on the conditional dependencies that underwrite the ensemble dynamics generating outcomes. the outcomes in question here pertain to a regional outbreak. this can be regarded as a generative model for the first wave of an epidemic in a large city or metropolis. this section considers variational model inversion and comparison, under hierarchical models. in other words, it considers the distinction between (first level) models of an outbreak in one country and (second level) models of differences among countries, in terms of model parameters. the second section briefly surveys the results of second level (between-country) modelling, looking at those aspects of the model that are conserved over countries (i.e., random effects) and those which are not (i.e., fixed effects). the third section then moves on to the dynamics and predictions for a single country; here, the united kingdom. it considers the likely outcomes over the next few weeks and how confident one can be about these outcomes, given data from all countries to date. this section drills down on the parameters that matter in terms of affecting death rates. it presents a sensitivity analysis that establishes the contribution of parameters or causes in the model to eventual outcomes. it concludes by looking at the effects of social distancing and herd immunity. the final section concludes with a consideration of predictive validity by comparing predicted and actual outcomes. this section describes the generative model summarised schematically in figure , while the data used to invert or fit this model are summarised in figure . these data comprise global (worldwide) timeseries from countries and regions from the initial reports of positive cases in china to the current day . the generative model is a mean field model of ensemble dynamics. in other words, it is a state space model where the states correspond to the sufficient statistics (i.e., parameters) of a probability distribution over the states of an ensemble or population-here, a population of people who are in mutual contact at some point in their daily lives. this kind of model is used routinely to model populations of neurons, where the ensemble dynamics are cast as density dynamics, under gaussian assumptions about the probability densities; e.g., (marreiros et al., ). in other words, a model of how the mean and covariance of a population affects itself and the means and covariances of other populations. here, we will focus on a single population and, crucially, use a discrete state space model. this means that we will be dealing with the sufficient statistics (i.e. expectations) of the probability of being in a in brief, this compartmental model generates timeseries data based on a mean field approximation to ensemble or population dynamics. the implicit probability distributions are over four latent factors, each with four levels or states. these factors are sufficient to generate measurable outcomes; for example, the number of new cases or the proportion of people infected. the first factor is the location of an individual, who can be at home, at work, in a critical care unit (ccu) or in the morgue. the second factor is infection status; namely, susceptible to infection, infected, infectious or immune. this model assumes that there is a progression from a state of susceptibility to immunity, through a period of (pre-contagious) infection to an infectious (contagious) status. the third factor is clinical status; namely, asymptomatic, symptomatic, acute respiratory distress syndrome (ards) or deceased. again, there is an assumed progression from asymptomatic to ards, where people with ards can either recover to an asymptomatic state or not. finally, the fourth factor represents diagnostic or testing status. an individual can be untested or waiting for the results of a test that can either be positive or negative. with this setup, one can be in one of four places, with any infectious status, expressing symptoms or not, and having test results or not. note that-in this construction-it is possible to be infected and yet be asymptomatic. however, the marginal distributions are not independent, by virtue of the dynamics that describe the transition among states within each factor. crucially, the transitions within any factor depend upon the marginal distribution of other factors. for example, the probability of becoming infected, given that one is susceptible to infection, depends upon whether one is at home or at work. similarly, the probability of developing symptoms depends upon whether one is infected or not. the probability of testing negative depends upon whether one is susceptible (or immune) to infection, and so on. finally, to complete the circular dependency, the probability of leaving home to go to work depends upon the number of infected people in the population, mediated by social distancing. the curvilinear arrows denote a conditioning of transition probabilities on the marginal distributions over other factors. these conditional dependencies constitute the mean field approximation and enable the dynamics to be solved or integrated over time. at any point in time, the probability of being in any combination of the four states determines what would be observed at the population level. for example, the occupancy of the deceased level of the clinical factor determines the current number of people who have recorded deaths. similarly, the occupancy of the positive level of the testing factor determines the expected number of positive cases reported. from these expectations, the expected number of new cases per day can be generated. a more detailed description of the generative model-in terms of transition probabilities-can be found in in the main text. figure . timeseries data. this figure provides a brief overview of the timeseries used for subsequent modelling, with a focus on the early trajectories of mortality. the upper left panel shows the distribution, over countries, of the number of days after the onset of an outbreakdefined as days before more than one case was reported. at the time of writing ( th april ), a substantial number of countries witnessed an outbreak lasting for more than days. the upper right panel plots the total number of deaths against the durations in the left panel. those countries whose outbreak started earlier have greater cumulative deaths. the middle left panel plots the new deaths reported (per day) over a -day period following the onset of an outbreak. the colours of the lines denote different countries. these countries are listed in the lower left panel, which plots the cumulative death rate. china is clearly the first country to be severely affected, with remaining countries evincing an accumulation of deaths some days after china. the middle right panel is a logarithmic plot of the total deaths against population size in the initial ( -day) period. interestingly, there is little correlation between the total number of deaths and population size. however, there is a stronger correlation between the total number of cases reported (within the first days) and the cumulative deaths as shown in lower right panel. in this period, germany has the greatest ratio of total cases to deaths. countries were included if their outbreak had lasted for more than days and more than deaths had been reported. the timeseries were smoothed with a gaussian kernel (full width half maximum of two days) to account for erratic reporting (e.g., recording deaths over the weekend). particular state at any one time. this renders the model a compartmental model (kermack et al., ) , where each state corresponds to a compartment. these latent states evolve according to transition probabilities that embody the causal influences and conditional dependencies that lend an epidemic its characteristic form. our objective is to identify the right conditional dependencies-and form posterior beliefs about the model parameters that mediate these dependencies. having done this, we can then simulate an entire trajectory into the distant future, even if we are only given data about the beginning of an outbreak . the model considers four different sorts of states (i.e., factors) that provide a description of any individual-sampled at random-that is sufficient to generate the data at hand. in brief, these factors were chosen to be as conditionally independent as possible to ensure an efficient estimation of the model parameters . the four factors were an individual's location, infection status, clinical status and diagnostic status. in other words, we considered that any member of the population can be characterised in terms of where they were, whether they were infected, infectious or immune, whether they were showing mild and severe or fatal symptoms, and whether they had been tested with an ensuing positive or negative result. each of these factors had four levels. for example, the location factor was divided into home, work, critical care unit, and the morgue. these states should not be taken too literally. for example, home stands in for anywhere that has a limited risk of exposure to, or contact with, an infected person (e.g., in the domestic home, in a non-critical hospital bed, in a care home, etc). work stands in for anywhere that has a larger risk of exposure to-or contact with-an infected person and therefore covers non-work activities, such as going to the supermarket or participating in team sports. similarly, designating someone as severely ill with acute respiratory distress syndrome (ards) is meant to cover any life-threatening conditions that would invite admission to intensive care. having established the state space, we can now turn to the causal aspect of the dynamic causal model. the causal structure of these models depends upon the dynamics or transitions from one state or another. it is at this point that a mean field approximation can be used. mean field approximations are used widely in physics to approximate a full (joint) probability density with the product of a series of marginal densities (bressloff & newby, ; marreiros et al., ; schumacher et al., ; zhang et al., ) . in this case, the factorisation is fairly subtle: we will factorise the transition probabilities, such that the probability of moving among states-within each factor-depends upon the marginal distribution of other factors (with one exception). for example, the probability of developing symptoms when asymptomatic depends on, and only on, the probability that i am infected. in what follows, we will step through the conditional probabilities for each factor to show how the model is put together (and could be changed). the first factor has four levels, home, work, ccu and the morgue. people can leave home but will always return (with unit probability) over a day. the probability of leaving home has a (prior) baseline rate of one third but is nuanced by any social distancing imperatives. these imperatives are predicated on the proportion of the population that is currently infected, such that the social distancing parameter (an exponent) determines the probability of leaving home . for example, social distancing is modelled as the propensity to leave home and expose oneself to interpersonal contacts. this can be modelled with the following transition probability: this means that the probability of leaving home, given i have no symptoms, is the probability i would have gone out normally, multiplied by a decreasing function of the proportion of people in the population who are infected. formally, this proportion is the marginal probability of being infected, where the marginal probability of a factor is an average over the remaining factors. the marginal probability p l of the location factor is as follows: where the final four equalities define each factor or state in the model. the parameters in this social distancing model are the probability of leaving home every day (θ out ) and the social distancing exponent (θ sde ). the only other two places one can be are in a ccu or the morgue. the probability of moving to critical care depends upon bed (i.e., hospital) availability, which is modelled as a sigmoid function of the occupancy of this state (i.e., the probability that a ccu bed is occupied) and a bed capacity parameter (a threshold). if one has severe symptoms, then one stays in the ccu. finally, the probability of moving to the morgue depends on, and only on, being deceased. note that all these dependencies are different states of the clinical factor (see below). this means we can write the transition probabilities among the location factor for each level of the clinical factor as follows (with a slight abuse of notation): here, the columns and rows of each transition probability matrix are ordered: home, work, ccu, morgue. the column indicates the current location and the row indicates the next location. parameter θ cap is bed capacity threshold and is a decreasing sigmoid function. in brief, these transition probabilities mean that i will go out when asymptomatic, unless social distancing is in play. however, when i have symptoms i will stay at home, unless i am hospitalised with acute respiratory distress. i remain in critical care unless i recover and go home or die and move to the morgue, where i stay. technically, the morgue is an absorbing state. in a similar way, we can express the probability of moving between different states of infection (i.e., susceptible, infected, infectious and immune) as follows: these transition probabilities mean that when susceptible, the probability of becoming infected depends upon the number of social contacts-which depends upon the proportion of time spent at home. this dependency is parameterised in terms of a transition probability per contact (θ trn ) and the expected number of contacts at home (θ rin ) and work (θ rou ) . once infected, one remains in this state for a period of time that is parameterised by a transition rate (θ inf ). this parameterisation illustrates a generic property of transition probabilities; namely, an interpretation in terms of rate constants and, implicitly, time constants. the rate parameter θ is related to the rate constant κ and time constant τ according to: in other words, the probability of staying in any one state is determined by the characteristic length of time that state is occupied. this means that the rate parameter above can be specified, a priori, in terms of the number of days we expect people to be infected, before becoming infectious. similarly, we can parameterise the transition from being infectious to being immune in terms of a typical period of being contagious, assuming that immunity is enduring and precludes reinfection . note that in the model, everybody in the morgue is treated as having acquired immunity. the transitions among clinical states depend upon both the infection status and location as follows: ( ) ( ) the transitions among clinical states (i.e., asymptomatic, symptomatic, ards and deceased) are relatively straightforward: if i am not infected (i.e., susceptible or immune) i will move to the asymptomatic state, unless i am dead. however, if i am infected (i.e., infected or infectious), i will develop symptoms with a particular probability (θ dev ). once i have developed symptoms, i will remain symptomatic and either recover to an asymptomatic state or develop acute respiratory distress with a particular probability (θ sev ). the parameterisation of these transitions depends upon the typical length of time that i here, inf trn infectious p p θ = − ⋅ can be interpreted as a probability of eluding infection with each interpersonal contact, such that the probability of remaining uninfected after θ r contacts is given by p θ r. note, that there is no distinction between people at home and at work; both are equally likely to be infectious. we can now assemble these transition probabilities into a probability transition matrix, and iterate from the first day to some time horizon, to generate a sequence of probability distributions over the joint space of all factors: notice that this is a completely deterministic state space model, because all the randomness is contained in the probabilities. notice also that the transition probability matrix t is both state and time dependent, because the transition probabilities above depend on marginal probabilities. in this approximation, the number of contacts i make is a weighted average of the number of people i could infect at home and the number of people i meet outside, per day, times the number of days i am contagious. the effective reproduction rate is not a biological rate constant. however, it is a useful epidemiological summary statistic that indicates how quickly the disease spreads through a population. when less than one, the infection will decay to an endemic equilibrium. we will use this measure later to understand the role of herd immunity. this completes the specification of the generative model of latent states. a list of the parameters and their prior means (and variances) is provided in table . notice that all of the parameters are scale parameters, i.e., they are rates or probabilities that cannot be negative. to enforce these positivity constraints, one applies a log transform to the parameters during model inversion or fitting. this has the advantage of being able to simplify the numerics using gaussian assumptions about the prior density (via a lognormal assumption). in other words, although the scale parameters are implemented as probabilities or rates, they are estimated as log parameters, denoted by note that prior variances are specified for log parameters. for example, a variance of / corresponds to a prior confidence interval of ~ % and can be considered weakly informative. these prior expectations should be read as the effective rates and time constants as they manifest in a real-world setting. for example, a three-day period of contagion is shorter than the period that someone might be infectious (wölfel et al., ) , on the (prior) assumption that they will self-isolate, when they realise they could be contagious. further parameters are required to generate data, such as the size of the population and the number of people who are initially it is revealing to note that the number of model parameters pertaining to pcr testing matches the number of parameters mediating the epidemiology per se. this reflects the fact that the generative model has to consider every aspect of how data are generated. in order to leverage the information in new positive tests, it is necessary to think carefully about all the parameters that contribute to these data; for example, the probability of being tested and the selection bias towards testing people who are more likely to be infected. crucially, this bias has to be estimated during model inversion and could vary substantially from country to country. although not implemented in this report, subsequent distinctions between pillar and test data would be a nice example of different selection biases. this speaks to the importance of modelling pillar and as distinct data modalities. from a technical perspective, equipping standard epidemiological models with an 'observation model' can be regarded as building a complete dynamic causal model. the key thing to bear in mind here is that the parameters of so-called observation models have to be treated in exactly the same way as epidemiological parameters, because they could show conditional dependencies. in dynamic causal modelling, all unknown parameters are treated in a uniform way to maximise (a free energy bound on) marginal likelihood. notice that this model is configured for new cases that are reported based on buccal swabs (i.e., am i currently infected?), not tests for antibody or immunological status. a different model would be required for forthcoming tests of immunity (i.e., have i been infected?). furthermore, one might consider the sensitivity and specificity of any test by including sensitivity and specificity in ( . ). for example, in tests may be false negatives; especially, when avoiding bronchoalveolar lavage to minimise risk to clinicians: wang et al., b. detection of sars-cov- in different types of clinical specimens. jama. added in revision: the reproduction ratio in this report was based upon an approximation to the expected number of people that i might infect, if i was infectious. in subsequent reports, the reproduction ratio was brought into line with more formal definitions, based on the geometric rate of increase in the prevalence of infection and the period of contagion. a minimum reproduction ratio (r) of nearly zero in this report corresponds to about . in subsequent (and other) reports. shedding of covid- viral rna from sputum can outlast the end of symptoms. seroconversion occurs after - days but is not necessarily followed by a rapid decline of viral load. infected (θ n , θ n ) , which parameterise the initial state of the population (where ⊗ denotes a kronecker tensor product): in this technical report, we will choose a simpler option that treats a pandemic as a set of linked point processes that can be modelled as rare events. in other words, we will focus on modelling a single outbreak in a region or city and treat the response of the 'next city' as a discrete process post hoc. this simplifies the generative model; in the sense we only have to worry about the ensemble dynamics of the population that comprises one city . a complimentary perspective on this choice is that we are trying to model the first wave of an epidemic as it plays out in the first city to be affected. any second wave can then be treated as the first wave of another city or region. under the initial conditions, the population size can be set, a priori, to , , ; noting that a small city comprises (by definition) a hundred thousand people, while a large city can exceed million. this population parameter is a prior that is updated based on the available data, providing an estimate of the "effective population" size. effective population is defined here as the proportion of the total population who are susceptible to infection, and therefore participate in the outbreak. the assumption that the effective population size reflects the total population of a country is a hypothesis that we will test later . for clarity, we are not implying that the remainder of the population classed as "not susceptible" are immune or resistant to covid- , rather there exists a sub-population who do not take part in the current outbreak for any of a variety of reasons that may include being shielded or geographically isolated from infected cases. furthermore, as the effective population (and other parameters) are estimated directly from the data, they will therefore reflect the source of the information. at the time of writing, in the uk this was dominated by the london outbreak. finally, as all parameters pertain to the effective population, proportions (or probabilities)-such as population immunityrequire appropriate scaling to be expressed as a percentage of the total (census) population. the likelihood or observation model the outcomes considered in figure are new cases (of positive tests and deaths) per day. these can be generated by multiplying the appropriate probability by the (effective) population size. the appropriate probabilities here are just the expected occupancy of positive test and deceased states, respectively. because we are dealing with large populations, the likelihood of any observed daily count has a binomial distribution that can be approximated by a gaussian density . here, outcomes are counts of rare events with a small probability π << of occurring in a large population of size n >> . for example, the likelihood of observing a timeseries of daily deaths can be expressed as a function of the model parameters as follows: the advantage of this limiting (large population) case is that a (variance stabilising) square root transform of the data counts renders their variance unity. with the priors and likelihood model in place, we now have a full joint probability over causes (parameters) and consequences (outcomes). this is the generative model ( , ) ( | ) ( ) one can now use standard variational techniques (friston et al., ) to estimate the posterior over model parameters and evaluate a variational bound on the model evidence or marginal likelihood. mathematically, this is expressed as follows: table also includes a parameter for the proportion of people who are initially immune, which we will call on later. these expressions show that maximising the variational free energy f with respect to an approximate posterior q(ϑ) renders the kullback-leibler (kl) divergence between the true and approximate posterior as small as possible. at the same time, the free energy becomes a lower bound on the log evidence. the free energy can then be used to compare different models, where any differences correspond to a log bayes factor or odds ratio (kass & raftery, ; winn & bishop, ) . one may be asking why we have chosen this particular state space and this parameterisation? are there alternative model structures or parameterisations that would be more fit for purpose? the answer is that there will always be a better model, where 'better' is a model that has more evidence. this means that the model has to be optimised in relation to empirical data. this process is known as bayesian model comparison based upon model evidence (winn & bishop, ) . for example, in the above model we assumed that social distancing increases as a function of the proportion of the population who are infected ( . ). this stands in for a multifactorial influence on social behaviour that may be mediated in many ways. for example, government advice, personal choices, availability of transport, media reports of 'panic buying' and so on. so, what licenses us to model the causes of social distancing in terms of a probability that any member of the population is infected? the answer rests upon bayesian model comparison. when inverting the model using data from countries with more than deaths (see figure ), we obtained a log evidence (i.e., variational free energy) of - natural units (nats). when replacing the cause of social distancing with the probability of encountering someone with symptoms-or the number of people testing positive-the model evidence fell substantially to - and - nats, respectively. in other words, there was overwhelming evidence in favour of infection rates as a primary drive for social distancing, over and above alternative models. we will return to the use of bayesian model comparison later, when asking what factors determine differences between each country's response to the pandemic. table lists all the model parameters; henceforth, dcm parameters. in total, there are dcm parameters. this may seem like a large number to estimate from the limited amount of data available (see figure ). the degree to which a parameter is informed by the data depends upon how changes in the parameter are expressed in data space. for example, increasing the effective population size will uniformly elevate the expected cases per day. conversely, decreasing the number of initially infected people will delay the curve by shifting it in time. in short, a parameter can be identified if it has a relatively unique expression in the data. this speaks to an important point, the information in the data is not just in the total count-it is in the shape or form of the transient . on this view, there are many degrees of freedom in a timeseries that can be leveraged to identify a highly parameterised model. the issue of whether the model is over parameterised or under parameterised is exactly the issue resolved by bayesian model comparison; namely, the removal of redundant parameters to suppress model complexity and ensure generalisation: see ( . ) . one therefore requires the best measures of model evidence. this is the primary motivation for using variational bayes; here, variational laplace (friston et al., ) . the variational free energy, in most circumstances, provides a better approximation than alternatives such as the widely used akaike information criteria and the widely used bayesian information criteria (penny, ). one special aspect of the model above is that it has absorbing states. for example, whenever one enters the morgue, becomes immune, dies or has a definitive test result, one stays in that state: see figure . this is important, because it means the long-term behaviour of the model has a fixed point. in other words, we know what the final outcomes will be. these outcomes are known as endemic equilibria. this means that the only uncertainty is about the trajectory from the present point in time to the distant future. we will see later that-when quantified in terms of bayesian credible intervals-this uncertainty starts to decrease as we go into the distant future. this should be contrasted with alternative models that do not parameterise the influences that generate outcomes and therefore call upon exogenous inputs (e.g., statutory changes in policy or changes in people's behaviour). if these interventions are unknown, they will accumulate uncertainty over time. by design, we elude this problem by including everything that matters within the model and parameterising strategic responses (like social distancing) as an integral part of the transition probabilities. we have made the simplifying assumption that every country reporting new cases is, effectively, reporting the first wave of an affected region or city. clearly, some countries could suffer simultaneous outbreaks in multiple cities. this is accommodated by an effective population size that could be greater than the prior expectation of million. this is an example of finding a simple model that best predicts outcomes-that may not be a veridical reflection of how those outcomes were actually generated. in other words, we will assume that each country behaves as if it has a single large city of at-risk denizens. in the next section, we look at the parameter estimates that obtain by pooling information from all countries, with a focus on between country differences, before turning to the epidemiology of a single country (the united kingdom). hitherto, we have focused on a generative model for a single city. however, in a pandemic, many cities will be affected. this calls for a hierarchical generative model that considers the response of each city at the first level and a global response at the second. this is an important consideration because it means, from a bayesian perspective, knowing what happens elsewhere places constraints (i.e., bayesian shrinkage priors) on estimates of what is happening in a particular city. clearly, this rests upon the extent to which certain model parameters are conserved from one city to another-and which are idiosyncratic or unique. this is a problem of hierarchical bayesian modelling or parametric empirical bayes (friston et al., ; kass & steffey, ). in the illustrative examples below, we will adopt a second level model in which key (log) parameters are sampled from a gaussian distribution with a global (worldwide) mean and variance. from the perspective of the generative model, this means that to generate a pandemic, one first samples city-specific parameters from a global distribution, adds a random effect, and uses the ensuing parameters to generate a timeseries for each city. this section considers the modelling of country-specific parameters, under a simple (general linear) model of between-country effects. this (second level) model requires us to specify which parameters are shared in a meaningful way between countries and which are unique to each country. technically, this can be cast as the difference between random and fixed effects. designating a particular parameter as a random effect means that this parameter was generated by sampling from a countrywide distribution, while a fixed effect is unique to each country. under a general linear model, the distribution for random effects is gaussian. in other words, to generate the parameter for a particular country, we take the global expectation and add a random gaussian variate, whose variance has to be estimated under suitable hyperpriors. furthermore, one has to specify systematic differences between countries in terms of independent variables; for example, does the latitude of a country have any systematic effect on the size of the at-risk population? the general linear model used here comprises a constant (i.e., the expectation or mean of each parameter over countries), the (logarithms of) total population size, and a series of independent variables based upon a discrete sine transform of latitude and longitude. the latter variables stand in for any systematic and geopolitical differences among countries that vary smoothly with their location. notice that the total population size may or may not provide useful constraints on the effective size of the population at the first level. under this hierarchical model, a bigger country may have a transport and communication infrastructure that could reduce the effective (at risk) population size. a hint that this may be the case is implicit in figure , where there is no apparent relationship between the early incidence of deaths and total population size. in the examples below, we treated the number of initial cases and the parameters pertaining to testing as fixed effects and all remaining parameters as random effects. the number of initial infected people determines the time at which a particular country evinces its outbreak. although this clearly depends upon geography and other factors, there is no a priori reason to assume a random variation about an average onset time. similarly, we assume that each country's capacity for testing was a fixed effect; thereby accommodating non-systematic testing or reporting strategies . note that in this kind of modelling, outcomes such as new cases can only be interpreted in relation to the probability of being tested and the availability of tests . with this model in place, we can now use standard procedures for parametric empirical bayesian modelling (friston et al., ; kass & steffey, ) to estimate the second level parameters that couple between-country independent variables to country-specific parameters of the dcm. however, there are a large number of these parameters-that may or may not contribute to model evidence. in other words, we need some way of removing redundant parameters based upon bayesian model comparison. this calls upon another standard procedure called . each of these models corresponds to a particular combination of parameters that have been 'switched off', by shrinking their prior variance to zero. by averaging the posterior estimates in proportion to the evidence for each model, -known as bayesian model averaging (hoeting et al., )-we can eliminate redundant parameters and thereby provide a simpler explanation for differences among countries. this is illustrated in the lower panels, which show the posterior densities before (left) and after (right) bayesian model reduction. these estimates are shown in terms of their expectation or maximum a posteriori (map) value (as blue bars), with % bayesian credible intervals (as pink bars). the first parameters are the global expectations of the dcm parameters. the remaining parameters are the coefficients that link various independent variables at the second level to the parameters of the transition probabilities at the first. note that a substantial number of second level parameters have been removed; however, many are retained. this suggests that there are systematic variations over countries in certain random effects at the country level. figure provides an example based upon the largest effect mediated by the independent variables. in this analysis, latitude (i.e., distance from the south pole) appears to reduce the effective size of an at-risk population. in other words, countries in the northern hemisphere have a smaller effective population size, relative to countries in the southern hemisphere. clearly, there may be many reasons for this; for example, systematic differences in temperature or demographics. the key thing to take from this analysis is the tight credible intervals on the parameters, when averaging in this way. according to this analysis, the number of effective contacts at home is about three people, while this increases by an order of magnitude to about people when leaving home. the symptomatic and acute respiratory distress periods have been estimated here at about five and days respectively, with a delay in testing of about two days. these are the values that provide the simplest explanation for the global data at hand-and are in line with empirical estimates . figure shows the country-specific parameter estimates for of the dcm parameters. these posterior densities were evaluated under the empirical priors from the parametric empirical bayesian analysis above. as one might expect-in in this instance, the models compared are at the second or between-country level. in other words, the models compared contained all combinations of (second level) parameters (a parameter is removed by setting its prior variance to zero). if the model evidence increases-in virtue of reducing model complexity-then this parameter is redundant. the upper panels show the relative evidence of the most likely models, in terms of log evidence (left panel) and the corresponding posterior probability (right panel). redundant parameters are illustrated in the lower panels by comparing the posterior expectations before and after the bayesian model reduction. the blue bars correspond to posterior expectations, while the pink bars denote % bayesian credible intervals. the key thing to take from this analysis is that a large number of second level parameters have been eliminated. these second level parameters encode the effects of population size and geographical location, on each of the parameters of the generative model. the next figure illustrates the nonredundant effects that can be inferred with almost % posterior confidence. here, the effective size of the population appears to depend upon the latitude of a country. the right panel shows the absolute values of the glm parameters in matrix form, showing that the effective size of the population was most predictable (the largest values are in white), though not necessarily predictable by total population size. the red circle highlights the parameter mediating the relationship illustrated in the left panel. or, indeed, a previous pandemic, such as the h h pandemic. we will return to this in the conclusion. https://en.wikipedia.org/wiki/greater_london however, there does appear to be some predictive validity to these that are addressed in an epilogue. note rather than dissect the predictive validity of each parameter and country, which is widely recognised as a challenging problem (moghadas, s.m., shoukat, a., fitzpatrick, m.c., wells, c.r., sah, p., pandey, a., sachs, j.d., wang, z., meyers, l.a., singer, b.h., galvani, a.p., . projecting hospital utilization during the covid- outbreaks in the united states. proc natl acad sci u s a , - .), we have provided some representative examples. a comprehensive analysis of this type would be beyond the scope of this report. it is also important to note that predictions based upon rate parameters and probabilities are a reflection of prior assumptions about these parameters, whereas predictions based upon the hidden states speak to the predictive validity of the dcm model structure (see below). virtue of the second level effects that survived bayesian model reduction-there are some substantial differences between countries in certain parameters. for example, the effective population size in the united states of america is substantially greater than elsewhere at about million (the population in new york state is about . million). the effective population size in the uk (dominated by cases in london) is estimated to be about . million (london has a population of about . million) . social distancing seems to be effective and sensitive to infection rates in france but much less so in canada. the efficacy of social distancing in terms of the difference between the number of contacts at home and work is notably attenuated in the united kingdom-that has the greatest number of home contacts and the least number of work contacts. other notable differences are the increased probability of fatality in critical care evident in china. this is despite the effective population size being only about . million. again, these assertions are not about actual states of affairs. these are the best explanations for the data under the simplest model of how those data were caused . this level of modelling is important because it enables the data or information from one country to inform estimates of the first level (dcm) parameters that underwrite the epidemic in another country . this is another expression of the importance of having a hierarchical generative model for making sense of the data. here, the generative model has latent causes that span different countries, thereby enabling the fusion of multimodal data from multiple countries (e.g., new test or death rates). two natural questions now arise. are there any systematic differences between countries in the parameters that shape epidemiological dynamics-and what do these dynamics or trajectories look like? this concludes our brief treatment of between country effects, in which we have considered the potentially important role of bayesian model reduction in identifying systematic variations in the evolution of an epidemic from country to country. the next section turns to the use of hierarchically informed estimates of dcm parameters to characterise an outbreak in a single country. this section drills down on the likely course of the epidemic in the uk, based upon the posterior density over dcm parameters afforded by the hierarchical (parametric empirical) bayesian analysis of the previous section (listed in table ). figure shows the expected trajectory of death rates, new cases, and occupancy of ccu beds over a six-month ( day) period. these (posterior predictive) densities are shown in terms of an expected trajectory and % credible intervals (blue line and shaded areas, respectively). the black dots represent empirical data (available at the time of writing). notice that the generative model can produce outcomes that may or may not be measured. here, the estimates are based upon the new cases and deaths in figure . the panels on the left show that our confidence about the causes of new cases is relatively high during the period for which we have data and then becomes uncertain in the future. this reflects the fact that the data are informing those parameters that shaped the initial transient, whereas other parameters responsible for the late peak and subsequent trajectory are less informed. notice that the uncertainty about cumulative deaths itself accumulates. on this analysis, we can be % confident that in five weeks, between , and , people may have died. relative to the total population, the proportion of people dying is very small; however, the cumulative death rates in absolute numbers are substantial, in relation to seasonal influenza (indicated with broken red lines). although cumulative death rates are small, they are concentrated within a short period of time, with near-identical ccu needs-with the risk of over-whelming available capacity (not to mention downstream effects from blocking other hospital admissions to prioritise the pandemic). the underlying latent causes of these trajectories are shown in figure . the upper panels reproduce the expected trajectories of the previous figure, while the lower panels show the underlying latent states in terms of expected rates or probabilities. for example, the social distancing measures are expressed in terms of an increasing probability of being at home, given the accumulation of infected cases in the population. during the peak expression of death rates, the proportion of people who are immune (herd immunity) increases to about % and then asymptotes at about %. this period is associated with a marked increase in the probability of developing symptoms (peaking at about weeks, after the first reported cases). interestingly, under these projections, the number of people expected to be in critical care should not exceed capacity: at its peak, the upper bound of the % credible interval for ccu occupancy is approximately , this is within the current ccu capacity of london (corresponding to the projected capacity of the temporary nightingale hospital in london, uk). it is natural to ask which dcm parameters contributed the most to the trajectories in figure . this is addressed using a sensitivity analysis. intuitively, this involves changing a particular parameter and seeing how much it affects the outcomes of interest. figure reports a sensitivity analysis of the parameters in terms of their direct contribution to cumulative deaths (upper panel) and how they interact (lower panel). these are effectively the gradient and hessian matrix (respectively) of predicted cumulative deaths. the bars in the upper panel pointing to the left indicate parameters that decrease total deaths. these include social distancing and bed availability, which are-to some extent-under our control. other factors that improve fatality rates include the symptomatic and acute respiratory distress periods and the probability of surviving outside critical care. these, at the present time, are not so amenable to intervention. note that initial immunity has no effect in this analysis because we clamped the initial values to zero with very precise priors. we will relax this later. first, we look at the effect of social distancing by simulating the ensemble dynamics under increasing levels of the social distancing exponent (i.e., the sensitivity of our social distancing and self-isolation behaviour to the prevalence of the virus in the community). it may be surprising to see that social distancing has such a small effect on total deaths (see upper panel in figure ). however, the contribution of social distancing is in the context of how the epidemic elicits other responses; for example, increases in critical care capacity. quantitatively speaking, increasing social distancing only delays the expression of morbidity in the population: it does not, in and of itself, decrease the cumulative cost (although it buys time to develop capacity, treatments, and primary interventions). this is especially the case if there is no effective limit on critical care capacity, because everybody who needs a bed can be accommodated. this speaks to the interaction between different causes or parameters in generating outcomes. in the particular case of the uk, the results in figure suggest that although social distancing is in play, self-isolation appears limited. this is because the number of contacts at home is relatively high (at over five); thereby attenuating the effect of social distancing. in other words, slowing the spread of the virus depends upon reducing the number of contacts by social distancing. however, this will only work if there is a notable difference between the number of contacts at home and work. one can illustrate this by simulating the effects of social distancing, when it makes a difference. figure reproduces the results in figure but for different levels of the social distancing parameter, while using the posterior expectation for contacts at home (of about four) from the bayesian parameter average. social distancing is expressed in terms of the probability of being found at home or work (see the panel labelled location). as we increase social distancing the probability and duration of being at home during the outbreak increases. this flattens the curve of death rates per day from about to a peak of about . this is the basis of the mitigation ('curve flattening') strategies that have been adopted worldwide. the effect of this strategy is to reduce cumulative deaths and prevent finite resources being overwhelmed. in this example, from about , to , , potentially saving about people. this is roughly four times the number of people who die in the equivalent period due to road traffic accidents. interestingly, these (posterior predictive) projections suggest that social distancing can lead to an endgame in which not everybody has to be immune (see the middle panel labelled infection). we now look at herd immunity using the same analysis. figure reproduces the results in figure using the united kingdom posterior estimates -but varying the initial (herd) immunity over levels from, effectively, to %. the effects of herd immunity are marked, with cumulative deaths ranging from about , with no immunity to very small numbers with a herd immunity of about %. the broken red lines in the upper right panel are the number of people dying from seasonal influenza (as in figure ) . these projections suggest that there is a critical level of herd immunity that will effectively avert an epidemic; in virtue of reducing infection rates, such that the spread of the virus decays exponentially. if we now return to figure , it can be seen that the critical level of herd immunity will, on the basis of these projections, be reached to weeks after the peak in death rates. at this point-according to the model-social distancing the key point to take from this figure is the quantification of uncertainty inherent in the credible intervals. in other words, uncertainty about the parameters propagates through to uncertainty in predicted outcomes. this uncertainty changes over time because of the nonlinear relationship between model parameters and ensemble dynamics. by model design, one can be certain about the final states; however, uncertainty about cumulative death rates itself accumulates. the mapping from parameters, through ensemble dynamics to outcomes is mediated by latent or hidden states. the trajectory of these states is illustrated in the next figure. note, only beds are ventilator/itu beds. we will use predictions-as opposed to projections-when appropriate, to emphasise the point that the generative model is not a timeseries model, in the sense that the unknown quantities (dcm parameters) do not change with time. this means the there is uncertainty about predictions in the future and the past, given uncertainty about the parameters (see figure ). this should be contrasted with the notion of forecasting or projection; however, predictions in the future, in this setting, can be construed as projections. starts to decline as revealed by an increase in the probability of being at work. we will put some dates on this trajectory by expressing it as a narrative in the conclusion. from a modelling perspective, the influence of initial herd immunity is important because it could form the basis of modelling the spread of the virus from city to another-and back again. in other words, more sophisticated generative . the expected death rate is shown in blue, new cases in red, predicted recovery rate in orange and ccu occupancy in yellow. the black dots correspond to empirical data. the lower four panels show the evolution of latent (ensemble) dynamics, in terms of the expected probability of being in various states. the first (location) panel shows that after about to weeks, there is sufficient evidence for the onset of an episode to induce social distancing, such that the probability of being found at work falls, over a couple of weeks to negligible levels. at this time, the number of infected people increases (to about %) with a concomitant probability of being infectious a few days later. during this time, the probability of becoming immune increases monotonically and saturates at about weeks. clinically, the probability of becoming symptomatic rises to about %, with a small probability of developing acute respiratory distress and, possibly death (these probabilities are very small and cannot be seen in this graph). in terms of testing, there is a progressive increase in the number of people tested, with a concomitant decrease in those untested or waiting for their results. interestingly, initially the number of negative tests increases monotonically, while the proportion of positive tests starts to catch up during the peak of the episode. under these parameters, the entire episode lasts for about weeks, or less than three months. the broken red line in the upper left panel shows the typical number of ccu beds available to a well-resourced city, prior to the outbreak. models can be envisaged, in which an infected person from one city is transported to another city with a small probability or rate. reciprocal exchange between cities, (and ensuing 'second waves') will then depend sensitively on the respective herd immunities in different regions. anecdotally, other major pandemics, without social isolation strategies, have almost invariably been followed by a second peak that is as high (e.g., the h n pandemic), or higher, than the first. under the current model, this would be handled in terms of a second region being infected by the first city and so on; like a chain of dominos or the spread of a bushfire (rhodes & anderson, ; zhang & tang, ). crucially, the effect of the second city (i.e., wave) on the first will be sensitive to the herd immunity established by the first wave. in this sense, it is interesting to know how initial levels of immunity shape a regional outbreak, under idealised assumptions. figure illustrates the interaction between immunity and viral spread as characterised by the effective reproduction rate, r (a.k.a. number or ratio); see ( . ). this figure plots the predicted death rates for the united kingdom and the accompanying fluctuations in r and herd immunity, where both are treated as outcomes of the generative model. the key thing to observe is that with low levels of immunity, r is fairly high at around . (current estimates of the basic reproduction ratio r , in the literature, range from . to . ). as soon as social distancing comes into play, r falls dramatically to almost . however, when social distancing is relaxed some weeks later, r remains low due to the partial acquisition of herd immunity, during the peak of the epidemic. note that herd immunity in this setting pertains to, and only to, the effective or at-risk population: % herd immunity a few months from onset would otherwise be overly optimistic, compared to other de novo pandemics; e.g., (donaldson et al., ). on the other hand, an occult herd immunity (i.e. not accompanied by symptoms) is consistent with undocumented infection and rapid dissemination (li et al., ) . note that this way of characterising the spread of a virus depends upon many variables (in this model, two factors and three parameters). and can vary from country to country. repeating the above analysis for china gives a much higher initial or basic reproduction rate, which is consistent with empirical reports (sanche et al., ). scenarios for a particular country. in the final section, we revisit the confidence with which these posterior predictive projections can be made. variational approaches-of the sort described in this technical report-use all the data at hand to furnish statistically efficient estimates of model parameters and evidence. this contrasts with alternative approaches based on cross-validation. in the cross-validation schemes, model evidence is approximated by cross-validation accuracy. in other words, the evidence for a model is scored by the log likelihood that some withheld or test data can be explained by the model. although model comparison based upon a variational evidence bound renders cross-validation unnecessary, one can apply the same procedures to demonstrate predictive validity. figure illustrates this by fitting partial timeseries from one country (italy) using the empirical priors afforded by the parametric empirical bayesian analysis. these partial data comprise the early phase of new cases. if the model has predictive validity, the ensuing posterior predictive density should contain the data that was withheld during estimation. figure presents an example of forward prediction over a -day period that contains the peak death rate. in this example, the withheld data are largely within the % credible intervals, speaking to the predictive validity of the generative model. there are two caveats here: first, similar analyses using very early timeseries from italy failed to predict the peak, because of insufficient (initial) constraints in the data. second, the credible intervals probably suffer from the well-known overconfidence problem in variational bayes, and the implicit mean field approximation (mackay, ) . we have rehearsed variational procedures for the inversion of a generative model of a viral epidemic-and have extended this model using hierarchical bayesian inference (parametric empirical bayes) to deal with the differential responses of each country, in the context of a worldwide pandemic. clearly, this narrative is entirely conditioned on the generative model used to make these predictions (e.g., the assumption of lasting immunity, which may or may not be true). the narrative is offered in a deliberately definitive fashion to illustrate the effect of resolving uncertainty about what will happen. it has been argued that many deleterious effects of the note further that the credible intervals can include negative values. this is an artefact of the way in which the intervals are computed: here, we used a first-order taylor expansion to propagate uncertainty about the parameters through to uncertainty about the outcomes. however, because this generative model is non-linear in the parameters, high-order terms are necessarily neglected. this narrative is not offered as a prediction -but as an example of the kind of predictions afforded by dynamic causal modelling. an aspect of these predictions is that they include systemic factors beyond the epidemiology per se. the best example of this is the above predictions about social distancing, which could be read as 'lockdown'; namely the probability that i will leave home. this highlights a key distinction between dynamic causal models and standard quantitative epidemiological modelling that treats things like 'lockdown' as interventions that are supplied to the model. in contrast, interventions such as social distancing and testing are modelled as an integral part of the process -and are estimated on the basis of the data at hand. one consequence of this is that one can make predictions about when 'interventions' -or their suspension -will occur in the future. the basic reproduction ratio is a constant that scores the spread of a contagion in a susceptible population. this corresponds to the effective reproduction ratio at the beginning of the outbreak, when everybody is susceptible. see figure uncertainty about what will happen. this is a key motivation behind procedures that quantify uncertainty, above and beyond being able to evaluate the evidence for different hypotheses about what will happen. one aspect of this is reflected in rhetoric such as "there is no clear exit strategy". it is reassuring to note that, if one subscribes to the above model, there is a clear exit strategy inherent in the self-organised mitigation afforded by herd immunity. for example, within a week of the peak death rate, there should be sufficient herd immunity to preclude any resurgence of infections in, say, london. the term 'self-organised' is used carefully here. this is because we are part of this process, through the effect of social distancing on our location, contact with infected people and subsequent dissemination of covid- . in other words, this formulation does not preclude strategic (e.g., nonpharmacological) interventions; rather, it embraces them as part of the self-organising ensemble dynamics . this technical report describes an initial implementation of the dcm framework to provide a generative model of a viral epidemic, and to demonstrate the potential utility of such modelling. clearly there are a number of ways this model could be refined. our hope in making it open source is that it will allow others to identify issues, contribute to improvements-and help facilitate objective comparisons with other models-using bayesian model comparison. there remain a number of outstanding issues: the generative model-at both the first and second level-needs to be explored more thoroughly. at the first level, this may entail the addition of other factors; for example, splitting the population into age groups or different classes of clinical vulnerability. procedurally, this should be fairly simple, by specifying the dcm parameters for each age group (or cohort) separately and precluding transitions between age groups (or cohorts). one could also consider the fine graining of states within each factor. for example, making a more careful distinction between being in and not in critical care (e.g., being in self-isolation, being in a hospital, community care home, rural or urban location and so on). at the between city or country level, the parameters of the general linear model could be easily extended to include a host of demographic and geographic independent variables. finally, it would be fairly straightforward to use increasingly fine-grained outcomes, using regional timeseries, as opposed to country timeseries (these data are currently available from: https://github.com/ cssegisanddata/covid- ). another plausible extension to the hierarchical model is to include previous outbreaks of mers and sars (middle east and severe acute respiratory syndrome, respectively) in the model. this would entail supplementing the timeseries with historical (i.e., legacy) data and replicating the general linear model for each type of virus. in effect, this would place figure . predictive validity. this figure uses the same format as figure ; however, here, the posterior estimates are based upon partial data, from early in the timeseries for an exemplar country (italy). these estimates were obtained under (parametric) empirical bayesian priors. the red dots show outcomes that were not used to estimate the expected trajectories (and credible intervals). this example illustrates the predictive validity of the estimates for a -day period following the last datapoint, which capture the rise to the peak of new cases. other words, more information about the dcm parameters can be installed through adjusting the prior expectations and variances. the utility of these adjustments would then be assessed in terms of model evidence. this may be particularly relevant as reliable data about bed occupancy, proportion of people recovered, etc becomes available. empirical priors or constraints on any parameter that shares characteristics with mers-cov and sars-cov. in terms of the model parameters-as opposed to model structure-more precise knowledge about the underlying causes of an epidemic will afford more precise posteriors. in a key aspect of the generative model used in this technical report is that it precludes any exogenous interventions of a strategic sort. in other words, the things that matter are built into the model and estimated as latent causes. however, prior knowledge about fluctuating factors, such as closing schools or limiting international air flights, could be entered by conditioning the dcm parameters on exogenous inputs. this would explicitly install intervention policies into the model. again, these conditions would only be licensed by an increase in model evidence (i.e., through comparing the evidence for models with and without some structured intervention). this may be especially important when it comes to modelling future interventions, for example, a 'sawtooth' social distancing protocol. a simple example of this kind of extension would be including a time dependent increase in the capacity for testing: at present, constraints on testing rates are assumed to be constant. a complementary approach would be to explore models in which social distancing depends upon variables that can be measured or inferred reliably (e.g., the rate of increase of people testing positive) and optimise the parameters of the ensuing model to minimise cumulative deaths. in principle, this should provide an operational equation that could be regarded as an adaptive (social distancing) policy, which accommodates as much as can be inferred about the epidemiology as possible. a key outstanding issue is the modelling of how one region (or city) affects another-and how the outbreak spreads from region to region. this may be an important aspect of these kinds of models; especially when it comes to modelling second waves as 'echoes' of infection, which are reflected back to the original epicentre. as noted above, the ability of these echoes to engender a second wave may be sensitively dependent on the herd immunity established during the first episode. herd immunity is therefore an important (currently latent or unobserved) state. this speaks to the importance of antibody testing in furnishing empirical constraints on herd immunity. in turn, this motivates antibody testing, even if the specificity and sensitivity of available tests are low. sensitivity and specificity are not only part of generative models, they can be estimated along with the other model parameters. in this setting, the role of antibody testing would be to provide data for population modelling and strategic advice-not to establish whether any particular person is immune or not (e.g., to allow them to go back to work). finally, it would be useful to assess the construct validity of the variational scheme adopted in dynamic causal modelling, in relation to schemes that do not make mean field approximations. these schemes usually rely upon some form of sampling (e.g., markov chain monte carlo sampling) and cross-validation. cross-validation accuracy can be regarded as a useful but computationally expensive proxy for model evidence and is the usual way that modellers perform automatic bayesian computation. given the prevalence of these sampling based (non-variational) schemes, it would be encouraging if both approaches converged on roughly the same predictions. the aim of this technical report is to place variational schemes on the table, so that construct validation becomes a possibility in the short-term future. the figures in this technical report can be reproduced using annotated ( ., ) ). the code is also compatible with gnu octave . . details about future developments of the software will be available from https://www.fil.ion.ucl.ac.uk/spm/covid- /. this epilogue was written three months after the report was submitted, providing an opportunity to revisit some of the predictions in light of actual outcomes. although the predictions in this report were used to illustrate the nature of the predictions supported by models that included social distancing, they can be used to assess the predictive validity of the dcm. subsequently, the dcm was optimized using bayesian model comparison. a crucial addition was the inclusion of heterogeneity in the response of the population to viral infection. however, even the simple dcm above accommodated sufficient heterogeneity-in terms of the distinction between an effective and total (census) population-to provide some accurate predictions. in brief, the shape and timing of the epidemic in london was predicted to within a few days. conversely, the number of fatalities and positive test results were overestimated by a factor of about . in what follows, we list the accurate and inaccurate predictions. we assume that the census population of london was . million . london's population is taken to be the effective population estimated to be . million (see table ) and social distancing is read as lockdown (i.e., the probability of leaving home). • "based on current data, reports of new cases in london are expected to peak on april " daily confirmed cases of coronavirus in london (and the uk) peaked on april . • "a peak in death rates around april (good friday this prediction corresponds to . % = % x . / . of the census population of london, which coincides with the consensus estimates at that time. "professor chris whitty admits he thinks at least % of the capital has been infected" (published on -april- ) . • "improvements should be seen by may , shortly after the may bank holiday, when social distancing will be relaxed." on may , the first black lives matter demonstrations started in london. this was followed by the first governmental relaxation of lockdown on may : "so, work from home if you can, but you should go to work if you can't work from home." (prime minister's address to the nation: -may- ) • "at this time [may ] herd immunity should have risen to about %" population immunity in the effective population corresponds to % x . / . = % seroprevalence in the census population, which had risen to . % in the previous week: "after making adjustments for the accuracy of the assay and the age and gender distribution of the population, the overall adjusted prevalence in london increased from . % in week to . % in weeks to and . % in week " (week ending may , ) . • "by june , death rates should have fallen to low levels with over % of people being immune" weekly reported deaths in london hospitals for the week ending june fell to (with positive tests)) . seroprevalence for this period was not reported. • "by june , social distancing [lockdown] will no longer be a feature of daily life." the second governmental relaxation of lockdown was announced on june and june , with an initial reopening of shops, and an easing of the two-metre social distancing rule: "[a]s the business secretary confirmed yesterday, we can now allow all shops to reopen from monday." (prime minister's statement that the coronavirus press conference: -june- ) "thanks to our progress, we can now go further and safely ease the lockdown in england. at every stage, caution will remain our watchword, and each step will be conditional and reversible. mr speaker, given the significant fall in the prevalence of the virus, we can change the two-metre social distancing rule, from th july." (prime minister's statement to the house: -june- ) inaccurate predictions these were overestimates; daily deaths in london peaked at on april with cumulative deaths at the time of writing ( -july- ) of , . this represents consistent overestimates by factors of . and . , respectively. this may reflect the fact that the data used in the report included regions in the united kingdom outside london. software is available from: https://www.fil.ion.ucl.ac.uk/spm/ covid- /. this technical report presents a dynamical causal model of the transmission dynamics of covid- . i believe this paper is one of very few (if any) that follow this type of approach which makes it interesting and an important contribution to the literature even after dozens of modeling papers on the topic have been published or are in the process of publication. the paper is well described and the results are interesting and present a new approach for assessing the role of multiple factors on the spread of covid- . however, the epidemic has advanced significantly, and it would be good to see how the results and perspectives are shaped by more recent data. authors should consider updating the paper with the most recent data available, and discuss how their analysis/conclusions are shaped by integrating additional data. if any results are presented, are all the source data underlying the results available to ensure full reproducibility? yes are the conclusions about the method and its performance adequately supported by the findings presented in the article? yes we have tried to revise the paper to preserve its original content (by limiting changes to the main text to clarify and unpack things). we have used new footnotes no. , , , , , and and a new section "posthoc evaluation of model predictions" to address issues that have arisen since submission (for example, the validity of predictions in light of actual outcomes). we hope this revised version is helpful in further clarifying our new approach. this is an interesting and expansive modelling paper from a group of scientists that do not primarily focus on modelling infectious diseases, i think contributions to epidemiology from other fields should always be welcomed and this is no exception. the techniques employed in this paper are less of a different type of model and more of an entirely different modelling framework. as such, i see part of my job in this review as trying to bridge the gaps between the language and techniques of dynamic causal modelling and infectious disease modelling. hopefully in doing so i am able to present any criticism in a way that both the authors and other infectious disease modellers are able to follow and understand. the dynamic causal model developed in this paper can be understood roughly as a stochastic compartmental seir model that has ) a "generative" model that describes movement between unobserved states over time (infection, recovery etc) and ) an "observational model" that describes the likelihood for the parameter values in the generative model given the observed data (in this case daily deaths and positive tests). the generative model has four components: location, which determines where you are and the contacts you make; infection, which is akin to the susceptible -exposed -infectious -recovered model used commonly; clinical, which determines the clinical presentation should you become infected; testing, which links your current infection status to the result of a swab test. you can be at various states within any of these four components at once, for example i could be an asymptomatic, infectious person at work that has not been tested. how i move between these states is governed by a matrix of probabilities that can be non-linear in time and as a response to feedback from other parameters within the model (for example my probability of observing lockdown can grow as more people die during the outbreak). i think ultimately the generative model is comparable to a complicated seir model and the next step in the mind of an infectious disease modeller is to use the likelihood from the observational model in a fitting method such as mcmc to generate samples from the posterior distribution of the generative model parameters. instead, dynamic causal modelling has a developed body of theory that allows for approximation of the analytical solution to the posterior of the model parameters that maximises the model evidence (marginal likelihood). this allows for immediate comparison of different generative model structures on the same data through selecting the model with the optimal log model evidence, which is also referred to as "variational free energy" (a similar process to the commonly used akaike or bayesian information criterion). this was refreshing to me as it can sometimes be difficult to obtain aic/bic after fitting your model depending on how you have fit it, such as in the probabilistic modelling language stan where you sometimes need to calculate the leave-one-out information criterion (loo-ic) yourself. another interesting methodological addition from the dynamic causal modelling framework is fitting the model to data from several different countries and then assigning model parameters as fixed or random effects, using a generalised linear model to estimate the between-country effects of certain covariates. in the manuscript the authors show the results of this process, finding a relationship between the latitude of a country and the effective population size of the outbreak inferred by the model. while, as the authors acknowledge, latitude here is very likely a proxy for other socio-economic variables, this approach could potentially yield interesting results using a wider selection of between-country effects or as a heuristic device to try and understand what factors are driving the model fit in each country. this is complemented with a technique called "bayesian model reduction", which efficiently prunes redundant parameters out of the model to simultaneously achieve model parsimony and perform a sensitivity analysis of sorts since it involves fixing the prior of each parameter and looking at the difference in model fit. to me, the framework of dynamic causal modelling seems to make available several tools that should be of interest to infectious disease modellers. it is not the case that infectious disease modellers don't already try to reduce models or compare them between countries, but what is attractive about the dynamic causal modelling approach is the coherency of the framework and the availability of software to perform the methods for models in general (although i think most infectious disease modellers would prefer to use r rather than matlab). at the very least, the methods employed in the dynamic causal modelling framework could be adapted to work with the more familiar combined compartmental model and mcmc approach. the methods in the dynamic causal modelling framework are heavily used and accepted in the field of neuroscience, so i don't think it's my job in this review to scrutinise them in particular outside of understanding them to the point where i can understand how the model in this particular paper was fitted. with the general modelling approach summarised i can move on to the specifics of the structure of the generative and observation models: in a similar way to aic/bic, i think i am correct in thinking that model selection using variational free energy only provides a relative score of model fit and not an objective score. choosing the best model out of a suite of models does not guarantee that this best model fits well, for this we need to turn to predictive validity and this is where i think the model laid out in the paper is at its weakest. below is the best-fitting model's prediction for london in full: "based on current data, reports of new cases in london are expected to peak on april , followed by a peak in death rates around april (good friday). at this time, critical care unit occupancy should peak, approaching-but not exceeding-capacity, based on current predictions and resource availability. at the peak of death rates, the proportion of people infected (in london) is expected to be about %, which should then be surpassed by the proportion of people who are immune at this time. improvements should be seen by may , shortly after the may bank holiday, when social distancing will be relaxed. at this time herd immunity should have risen to about %, about % of london's population will have been tested. just under half of those tested will be positive. by june , death rates should have fallen to low levels with over % of people being immune and social distancing will no longer be a feature of daily life." it's quite hard to tell if we are meant to interpret this as an example of what sort of narrative could be derived from the results of the model, or whether this is a genuine model prediction. if it is the latter, then i would expect to see mention of when the prediction was made, as well as plots showing the prediction (shown in figures and ) against the data which is now available. the authors do this for their predictions for italy ( figure ) but not london. i am writing this review on june th and at the time of writing the number of deaths on the th june was . without numbers given for the prediction it's hard to know if this counts as "low levels" or not, the th june was the beginning of week and the corresponding prediction of daily deaths in figure is near zero. perhaps more concerning than the prediction for deaths is the prediction for immunity. in the paper i find it quite difficult to tell what exactly is being spoken about when it comes to immunity. the model fits a parameter called "effective population" (θn) that i think could do with some further explanation, it seems to be the case that immunity is presented as the number of infections inferred by the model divided by the effective population. when the model was fitted to uk data it inferred an effective population size of ~ . million people. it's quite hard to tell but from figure , looking at the cumulative cases inferred by the model and the proportion of the population entering the immune category, it seems like the model has predicted that nearly all of the . million people in the effective population are now immune. here is what the authors say about the effective population parameter: "in this technical report, we will choose a simpler option that treats a pandemic as a set of linked point processes that can be modelled as rare events. in other words, we will focus on modelling a single outbreak in a region or city and treat the response of the 'next city' as a discrete process post hoc. this simplifies the generative model; in the sense we only have to worry about the ensemble dynamics of the population that comprises one city. a complimentary perspective on this choice is that we are trying to model the first wave of an epidemic as it plays out in the first city to be affected. any second wave can then be treated as the first wave of another city or region .under this choice, the population size can be set, a priori, to , , ; noting that a small city comprises (by definition)a hundred thousand people, while a large city can exceed million. note that this is a prior expectation, the effective population size is estimated from the data: the assumption that the effective population size reflects the total population of a country is a hypothesis (that we will test later)." it is true that you can use a model with a population size under million, look at the dynamics of the outbreak from the model output, and infer things about the potential effectiveness of social distancing, eventual likelihood of herd immunity, and so on, that would be true in a larger population. however, you would not fit a model to death data for all of the uk using a population parameter that is smaller than the population of the uk. i think the model output as shown in the manuscript is a best guess at the outbreak dynamics if the number of deaths and cases observed in a place with a population of million people were instead observed in a place with a population of . million. as a result of fitting to death rates for a population times bigger than the one in your model, you would expect to find that almost everyone is infected. since the writing of this manuscript, serological studies have started to emerge which estimate the percentage of the population that have been infected (which would correspond to the immune compartment in the model) . on the th may the ons estimated that around % of the uk have antibodies for covid- , rising to % in london. even acknowledging that serology studies are not perfect and that the ones performed so far have been quite small scale, this is really quite a different picture than the % population immunity presented by the model output. the picture is similar in serological studies across the world, even in healthcare workers in hard-hit cities like barcelona that would have faced constant exposure to infection. what is the result of fitting the model to uk deaths and reported cases with a fixed, actual value for the effective population? or at least using the uk population as the prior value? i think either a) the model output should be more clearly presented as an example or b) you should acknowledge that the model output gives predictions that seem very different from the emerging evidence the fitted probability that a person dies given that they are in the ccu (θfat) for china and italy is very high (nearly % and well over %). how well does this compare to actual observed mortality rates in ccus? for example, this paper , found % mortality in icus in lombardy, italy in early march. the uk data collated by the john hopkins covid- data repository that the authors use fetches data from here. the observation model could be improved by including a delay between the actual occurrence of death and its eventual reporting in the official statistics, sometimes it can take a couple of days for deaths to appear in the government figures. i think this could interfere with the model fit as it tries to align deaths and reported cases (which it currently reasons have both happened on that day). it is also important to consider the structure of the surveillance system when trying to fit to reported cases. in the uk for a good while tests were only undertaken on hospital admissions that were severe enough to warrant being admitted overnight (or at least that is what the official policy was). other countries like south korea had drive-through test centres. this is going to cause a huge discrepancy in how you should interpret changes in reported cases. it is strange that there is so much variation in some of the parameters between countries. for example, the contagious period is around day in china but around - days in france? what is the biological reasoning behind this? arguably there could be some genetic variation in the virus between countries but could that cause such a significant difference? is there any empirical evidence that supports differences in how long your are contagious between countries? the same goes for the numbers of contacts at home or contacts at work. people in the united kingdom are estimated to have around contacts at home, but the average size of uk households is just . . it would be good to link the output of these variables to any empirical data that is available to show that they are meaningful and do actually correspond to whatever data might be available. one of the countries with the lowest effective contacts in the household (~ . ) has a higher average household size than the uk of . . the variable for the probability of infection given contact (θtrn) is fairly stable apart from china and australia where it is relatively large and small, respectively. do the authors have any thoughts why this might be the case? the model does not include any kind of age structure. age has a large effect on the fatality of infection and should therefore be accounted for. countries with an older population would likely see a higher fatality rate. age could also influence the amount and types of contacts that people make, with more intergenerational contacts happening within the home and more intragenerational contacts happening at work or school. the model described in this paper is an interesting and important first step at putting together a model of infectious disease dynamics within the framework of dynamic causal modelling. however, when the particular model here is fit to data i don't think it displays that it has captured the dynamics of the outbreak well wherever it is able to be compared to separately collected bits of data such as seroprevalence or ccu mortality. i think what has happened in the model fitting process for the most part is that the variation introduced into the time series of deaths and reported cases due to differing surveillance and reporting structures, differing testing regimes, differing outbreak responses, and differing population demographics between countries have been accounted for within the generative model through between-country variation in parameters such as the effective population size, numbers of contacts at work (for example, do most people in china really have between and effective contacts at work?), ccu fatality, contagious period length, and others. the unfortunate reality is that with a flexible enough model (in terms of numbers of parameters) it is always possible to produce a fit that very closely matches the reported case and death data observed so far. the real test for this model is whether the estimated parameter values that can be compared to other sources of data match what we observe empirically and i think it is fairly obvious that this has not happened. sadly i don't think that i can recommend this paper for indexing as it currently stands because i don't think it is clear what it is trying to do. i think the easiest way of resolving this problem is for the authors to ask themselves the question "do i think the model predictions made for the uk in this paper are plausible or are they examples of predictions that can be made from the model?". if the predictions are examples then this paper is an introduction to disease modelling using dynamic causal modelling and the predictions should be more clearly labelled as examples. the paper could then be further improved by showing how methods such as the between-country parameter comparisons using the hierarchical glm correspond to the types of questions that disease modellers want to answer. alternatively, if the authors do think that the predictions made in this paper are accurate, then they need to be far more stringent comparing their predictions with data that has become available since they are made and have questions to answer regarding the gap between the % immunity in london that they predict and the % that has been estimated by the ons. that london may have already reached herd immunity has huge implications for future intervention policies, the most significant being that there is no danger of a second wave. if we behave as if there is % immunity (completely end social distancing etc.) but we are in fact well below herd immunity, then we will have likely caused the second wave through our own actions. compare we would like to thank you for the considerable time and effort you have spent reviewing our manuscript. your thoroughness and attention to detail, in what must be very busy and challenging times, has been very much appreciated. we were particularly impressed with the summary of the technical aspects of this work, which are useful and informed descriptions in their own right. we have tried to revise the paper to preserve its original content (by limiting changes to the main text to clarify and unpack things). we have used footnotes and a new 'to address issues that have arisen since submission (for example, the validity of predictions in light of actual outcomes). below are the replies to the comments, that for clarity we have grouped into key themes. we hope these revisions are what you had in mind: the primary purpose of this paper was to serve as a technical report, introducing a methodology that could be, and was, used to answer specific questions about epidemiological parameters and epidemiological model structure. to clarify this, we have emphasised that the narrative at the end of the paper is an example of the kind of predictions that can be made, rather than a definitive prediction per se (footnote ): "this narrative is not offered as a prediction -but as an example of the kind of predictions afforded by dynamic causal modelling. an aspect of these predictions is that they include systemic factors beyond the epidemiology per se. the best example of this is the above predictions about social distancing, which could be read as 'lockdown'; namely the probability that i will leave home. this highlights a key distinction between dynamic causal models and standard quantitative epidemiological modelling that treats things like 'lockdown' as interventions that are supplied to the model. in contrast, interventions such as social distancing and testing are modelled as an integral part of the process -and are estimated on the basis of the data at hand. one consequence of this is that one can make predictions about when 'interventions' -or their suspension -will occur in the future." regarding specific predictive validity, we thought it would be disingenuous to change the predictions in light of subsequent outcomes-or the procedures that were applied in subsequent reports. however, we have now added an extensive 'posthoc evaluation of model predictions' section in the revised version that addresses the predictions in light of current data. this section implicitly addresses the specific points about predictions in the reviewers' comments. we have also attempted to make the demarcation between a procedural and predictive contribution clearer throughout the text by including footnotes like the following (footnote ): "to reiterate, the purpose of this technical report was to introduce the variational procedures entailed by dynamic causal modelling in the setting of quantitative, epidemiological modelling. since this report was submitted, several papers have used procedures described in this report to address specific questions; for example, the impact of lockdown cycles, the effect of population fluxes among regional outbreaks, the efficacy of testing and tracing, and the impact of heterogeneous susceptibility and transmission. crucially, in line with a key message of this foundational paper, each successive application of the dynamic causal modelling leveraged bayesian model comparison to update the model as new data became available." we also take the opportunity to future-proof retrospective evaluations of the reproduction ratio with the following footnote : "added in revision: the reproduction ratio in this report was based upon an approximation to the expected number of people that i might infect, if i was infectious. in subsequent reports, the reproduction ratio was brought into line with more formal definitions, based on the geometric rate of increase in the prevalence of infection and the period of contagion. a minimum reproduction ratio (r) of nearly zero in this report corresponds to about . in subsequent (and other) reports." in addition to these, we have also incorporated a number of additional changes outlined below. it is clear that the "effective population" terminology, particularly in respect to immunity, represents a common source of confusion. to rectify this, we have made a number of changes throughout the paper. first, we have amended the "initial conditions and population size" section, splitting it and introducing a new subsection as follows: we have also annotated the legend to figure , and made the following change to immunity predictions, to clarify this further: we appreciate the number of suggestions to help refine or improve this model further. as surmised in the "predictive validity" section of your review, this report provides an initial technical description for the kind of analyses that could be used via the presented methodology. in a sense, it represents a proof of concept for this type of modelling, and we acknowledge there are many directions and improvements that could be made such as there remain a number of outstanding issues:" additionally, in a separate piece of work [ ] we have also formally compared an ode-based seir model to the dcm presented here. here the seir was developed originally by moghadas et al. [ ] to assess ccu projections due to covid- in the us. the seir model comprised states including asymptomatic and subclinical infected states, self-isolation, and separate states of hospitalization [ ]. we optimised parameters for both the seir and dcm using identical variational processes to those presented here. taking data from seven european countries including the uk, we found that the approximate model evidence or free energy provided very strong support for the dcm as compared to the seir model, suggesting that marginal state occupancy was important when accounting for those data. in particular log bayes factors of > was evidenced for all seven datasets. this comparative analysis is currently under review. we thank the reviewer for highlighting this. we are aware that delays in reporting deaths and reporting of statistics over weekends do represent potential confounds to the observed time series data. in this work, we perform smoothing of time series by several days to deal with these delays in reporting. delays in reporting pcr testing were modelled explicitly in terms of a 'waiting for a test' state because entry into this state depends upon testing capacity. conversely, a simple delay in reporting a death can be accommodated by an increase in effective dwell time in critical care. one could consider a dcm that modelled the delay in reporting deaths explicitly-and then use bayesian model comparison to compare models with and without delays. we did not do this; however, the conditional dependencies between an additional delay parameter and the existing parameters would probably reduce the marginal likelihood (i.e., bayesian model evidence) of an extended dcm. we agree that differences in testing and reporting strategies will impact the data. in the model presented, the testing rate parameter accounts for some of these differences. we have added the following footnote to emphasise the importance of this part of the model. first a disclaimer is that these assertions (for example fig. , showing differences among countries) are not about actual states of affairs. these are the best explanations for the data available at the time, under the simplest model of how those data were caused. however, there does appear to be some degree of predictive validity; for example, the predicted ccu mortality rate in the uk in april (at the time of writing of the paper) of about %, was close to data published on the th april by the intensive care national audit and research centre (critical care mortality = . % [ ]). regarding the italian data from lombardy, whilst the mortality rate was lower ( %), the data was acquired earlier on in the pandemic (february to march ) before the peak in cases. rather than dissect the predictive validity of each parameter and country, which is widely recognised as an extremely challenging problem [ ], we would reiterate that this paper is intended as a technical report for dcm, and provides examples of the types of questions that could be addressed using this method. to clarify these points, we have modified the following in the "parametric empirical bayes and hierarchical modelling section": [ ] https://en.wikipedia.org/wiki/greater_london ******************************************************************************************** posthoc evaluation of model predictions this section was written three months after the report was submitted, providing an opportunity to revisit some of the predictions in light of actual outcomes. although the predictions in this report were used to illustrate the nature of the predictions supported by models that included social distancing, they can be used to assess the predictive validity of the dcm. subsequently, the dcm was optimized using bayesian model comparison. a crucial addition was the inclusion of heterogeneity in the response of the population to viral infection. however, even the simple dcm above accommodated sufficient heterogeneity-in terms of the distinction between an effective and total (census) population-to provide some accurate predictions. in brief, the shape and timing of the epidemic in london was predicted to within a few days. conversely, the number of fatalities and positive test results were overestimated by a factor of about . in what follows, we list the accurate and inaccurate predictions. we assume that the census population of london was . million [ ] . london's population is taken to be the effective population estimated to be . million (see table ) and social distancing is read as lockdown (i.e., the probability of leaving home). "at the peak of death rates [april ], the proportion of people infected (in london) is expected to be about %" ○ this prediction corresponds to . % = % x . / . of the census population of london, which coincides with the consensus estimates at that time. "professor chris whitty admits he thinks at least % of the capital has been infected" (published on -april- ) [ ] . "improvements should be seen by may , shortly after the may bank holiday, when social distancing will be relaxed." ○ on may , the first black lives matter demonstrations started in london. this was followed by the first governmental relaxation of lockdown on may : "so, work from home if you can, but you should go to work if you can't work from home." (prime minister's address to the nation: -may- ) [ ] "at this time [may ] herd immunity should have risen to about %" ○ population immunity in the effective population corresponds to % x . / . = % seroprevalence in the census population, which had risen to . % in the previous week: "after making adjustments for the accuracy of the assay and the age and gender distribution of the population, the overall adjusted prevalence in london increased from . % in week to . % in weeks to and . % in week " (week ending may , ) [ ]. "by june , death rates should have fallen to low levels with over % of people being immune" ○ weekly reported deaths in london hospitals for the week ending june fell to (with positive tests)[ ]. seroprevalence for this period was not reported. "by june , social distancing [lockdown] will no longer be a feature of daily life." ○ the second governmental relaxation of lockdown was announced on june and june , with an initial reopening of shops, and an easing of the two-metre social distancing rule: "[a]s the business secretary confirmed yesterday, we can now allow all shops to reopen from monday." (prime minister's statement that the coronavirus press conference: -june- ) [ ] "thanks to our progress, we can now go further and safely ease the lockdown in england. at every stage, caution will remain our watchword, and each step will be conditional and reversible. mr speaker, given the significant fall in the prevalence of the virus, we can change the two-metre social distancing rule, from th july." (prime minister's statement to the house: -june- ) [ ] inaccurate predictions "about % of london's population will have been tested (may ). just under half of those ○ tested will be positive." this was an overestimate: % of the effective population corresponds to , = % x . x . positive tests. at the time of writing ( -july- ), only , people have tested positive in london [ ]-a quarter of the predicted number. from figure : peak daily death rate ( - ) with cumulative deaths of , ( , - , ) ○ these were overestimates; daily deaths in london peaked at on april with cumulative deaths at the time of writing ( -july- ) of , [ ] . this represents consistent overestimates by factors of . and . , respectively. this may reflect the fact that the data used in the report included regions in the united kingdom outside london. baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region estimating required'lockdown'cycles before immunity to sars-cov- : model-based analyses competing interests: no competing interests were disclosed reviewer expertise: mathematical epidemiology. author response jul we would like to thank you dr. chowell, for reviewing our manuscript and finding our approach interesting. we have now revised the paper, based on your and another reviewer's feedback, which is now available. key: cord- -acjskz authors: ruan, yongsen; luo, zhida; tang, xiaolu; li, guanghao; wen, haijun; he, xionglei; lu, xuemei; lu, jian; wu, chung-i title: on the founder effect in covid- outbreaks – how many infected travelers may have started them all? date: - - journal: natl sci rev doi: . /nsr/nwaa sha: doc_id: cord_uid: acjskz how many incoming travelers [i( ) at time , equivalent to the “founders” in evolutionary genetics] infected with sars-cov- who visit or return to a region could have started the epidemic of that region? i( ) would be informative about the initiation and progression of the epidemics. to obtain i( ), we analyze the genetic divergence among viral populations of different regions. by applying the “individual-output” model of genetic drift to the sars-cov- diversities, we obtain i( ) < , which could have been achieved by one infected traveler in a long-distance flight. the conclusion is robust regardless of the source population, the continuation of inputs (i(t) for t > ) or the fitness of the variants. with such a tiny trickle of human movement igniting many outbreaks, the crucial stage of repressing an epidemic in any region should, therefore, be the very first sign of local contagion when positive cases first become identifiable. the implications of the highly “portable” epidemics, including their early evolution prior to any outbreak, are explored in the companion study (ruan et al. ). region, within which the bulk of human interactions happen. relative to the within-region movement, a bordered region is lightly connected to the rest of the world. since the epidemic in any bordered region could have been started by one single infected traveler, or by , of them, we take the population genetic approach to analyzing the divergence among viral populations in relation to the "founder effect" [ ] . we shall let i t be the amount of input at time t (i.e., the number of infected people coming in an uninfected region). the crucial number is i , i.e., the first batch of input. the magnitude of i t is important in the public health practice. if i t has been large with continual input lasting for weeks, then a bordered region may be able to prevent the epidemic from being exported to (or being imported from) other regions, solely by restricting human movements out of (or into) its borders. on the other hand, if the epidemic in a region could be started with i < (and i t> ~ ), then sealing off either emigration or immigration would not be effective in stopping a pandemic. unless the bordered regions are maintaining zero infections, the danger would be coming mainly from within their borders. here, we aim to infer i t , in particular, in the early period of an epidemic. in this study, we use a population genetic framework [ ] . because the focus is the stochastic differentiation among viral populations, epidemiological models generally do not cover such topics. the genetic drift formulation used here also permits the calculation of the extinction probability of the invasion of the virus ( [ ] , ruan et al. ). epidemiological parameters, such as the number of uninfected individuals, the effects of quarantine and the development of immunity [ , ] , are not considered here as population differentiation takes place in the earliest stage of the invasion. during this stage, neither quarantine nor herd immunity has yet become a major factor in the outbreak. theory -to estimate i t , a conventional method is to inspect the changes in the population size of the viruses, n t [ , ] . viral population size corresponds to the number of infected individuals, assuming a viral clone in each person. because n t is only weakly dependent on i t , the conventional approach does not offer the resolution we seek for. it would be more informative to examine multiple populations for their differences in genetic polymorphism. the differences would depend strongly on i t at the very beginning of the epidemic ( fig. ). for studying population differentiation, the source population infecting the travelers needs to harbor genetic variants in non-trivial frequencies to yield informative data [ ] . for example, tang et al. [ ] reported the existence of two lineages that are distinguishable by two snps, one being a serine/lysine (s/l) polymorphism. according to ref. , the s lineage accounts for ~ % and the l lineage accounts for ~ % among the viral genomes they examined. for the ease of estimating i t 's, the variants should ideally be neutral in fitness. indeed, since variants under selection would have a short retention time in the population, snps are often neutral [ ] [ ] [ ] . while the fitness differential between the l and s variants remains unclear, our simulations show that the estimation of i t is only weakly dependent on selection (see below). the estimation of i as well as i t> are conducted for multiple viral populations, which should ideally originate from independent samples. among these populations, we model their differentiation as a function of i t . i t is not likely to be very large between regions (including the source) reachable only by air flight, each of which may carry at most a small number of infected passengers. as long as all extant populations are derived from the same source population, the estimates of i t are only weakly dependent on the actual genetic make-up of the source. for that reason, the source population needs not be known. the hypothesis is that the viral populations seeded by the infected travelers have experienced strong fluctuation in gene frequency. this may happen at the beginning of the epidemic when n t is small. soon afterwards, the fluctuation in gene frequencies would be quickly dampened as n t grows. the fluctuation in gene frequencies due to the random transmissions of genes is referred to as genetic drift [ , ] or the founder effects [ ] . the standard formulation of genetic drift by the wright-fisher model (or the alternative model of moran [ ] ) is not applicable for tracking the viral population. instead, we use the "individual output" model we previously proposed [ ] . all models assume discrete generations. based on the infection dynamics estimated in a recent study [ ] , we assume that each discrete generation is ~ days. if we use a longer or shorter generation time, the outcome would be similar as long as the progeny production is calibrated with the generation time. from one generation to the next, each individual produces k "descendants" (or infects k others) with the mean of e(k) and the variance of v(k). in the wright-fisher model, k follows the poisson distribution and v(k) is tied to e(k) [ ] . in the "individual output" model, k may follow any distribution, which is often measurable but not in any common form. e(k) dictates the population growth, n t , while v(k) determines the fluctuation in n t and in gene frequency. we will attempt to obtain e(k) and v(k) from the empirical data and, for a comparison, will also allow v(k) = e(k) to approximate the wright-fisher model. n t is a function of e(k), v(k) and i t . here, we assume i t to be a constant, hence, i t = i for all t's. at time t, if e(k) is not too small, e(n t ) would depend mainly on i t of the first few generations. in fact, the results are often similar whether there is constant input or not (i.e., i t = i , or i t = when t ≥ ). in other words, eq. ( ') below would yield similar results as eq. ( ) with reasonable accuracy, e(k) can be obtained from the growth trajectory of n t but i has to be obtained by a different means. while many of the assumptions such as exponential growth and the constancy of i t may hold for only a few generations, most of our results depend primarily on the dynamics of the first few generations. the actual trajectory of each population would also depend on v(k). using the simpler eq. ( '), ( ). to obtain i for eqs. ( ) or ( '), we have to model gene frequencies. using the example of the s/l polymorphism, we let x t be the frequency of the l lineage at time t. if the fitness of the s and l type is the same, then where x is the frequency in the source population. eqs. ( ) and ( ) will need some modifications if we use eq. ( ), or if we consider the fitness difference between l and s. (see supplement). the actual realization of x t in each population is obtained by iteration described here. we assume two types of viruses (l type and s type; [ ] ). the relative fitness of l type to s type is +s (s = represents no selection). in addition, there is a source population, in which the frequency of the l type is x . at generation t, there will be i t immigrants from the source population. i is the founder population size. a parameter t sets the time limit of immigration. thus, at generation t- , the numbers of the l type and s type are l t- and s t- respectively. also, n t- = l t- + s t- and x t- = l t- / n t- . after one generation, there will be i t (i t = i l + i s ; i l , i s are the numbers of l, s type, respectively) immigrants from the source population. in addition, n t- will increase to n t. thus, at generation t, the numbers of the l and s type are where is the progeny number of the i-th individual of either type. the distribution of will be defined in the next section. if there is selection, the number of l type will change as follows: at generation t, the population size and the frequency of l type are based on the definition above, we simulate the stochastic changes of the viral population until it reaches the th generation (i.e. t = ). since genetic drift is negligible when n t is large (e.g. > ), we simulate the trajectory by a deterministic model when n t > . to quantify the population differentiation, we calculate the pairwise fst values [ , ] , defined below. with x t and y t for a pair of populations, where ̅ = ( + )/ . if fst = , x t = y t and the two populations are identical in gene frequency. if fst = , the two populations are maximally differentiated with x t = and y t = , or vice versa. defining the parameter set (i , t, x , s) and the distribution of k as stated, the conventional wright-fisher model requires k (progeny number of an individual) to follow a poisson distribution with v(k) = e(k). here, we assume the spread of virus to be associated with the social network, which usually follows the power law [ , ] . specifically, we let k follow the zipf's law (a discrete power-law distribution; [ ] ): the estimate of the basic reproduction number (r ) of sars-cov- ranges from . to . [ ] [ ] [ ] . here, we focus on the early phase of the viral population growth by using r = . . the relationship between e(k) and r is as follows: where τ being the serial interval, g being the generation time. and τ is estimated to be ~ days [ , ] and and v(k) rather than the actual distribution. by setting v(k) so large, we ensure that the i estimate would be on the high side (see discussion). the estimation of i as well as i t> should be done on multiple viral populations that are independent samples from the same source. if they are not fully independent, then our estimates of i t would be conservative (i.e., over-estimation) since any exchange between populations should reduce the divergence. here, we generate two sets of data as shown in table in set ii, we assign gene frequencies to populations in table using the reported frequencies as a guide (gisaid (https://www.gisaid.org/); see supplement). these populations, distributed among continents, are as likely to be independently derived as we could ascertain. the choice is based on three criteria: ) the geography of the countries/regions and the distance between them; ) the timing of the documented onset of the epidemic; ) the abundance of dna sequences. we consult the frequencies in samples collected before late march , corresponding roughly to g in fig. . due to the rapidly changing data reporting (gisaid [ ] ), the frequency profile of set ii is plausibly realistic as reported in mid-april (see supplement). readers with access to the more up-to-date data can compare the new observations with the theoretical results to improve the estimation of i t . comparisons between simulations and data -in fig. , the fst distributions based on the datasets of table smaller range in fig. than that in fig. . in other words, with selection, the estimated i should be even smaller than indicated above. the simulation results are based on the distribution of k that follows the power law (see eqs. and ) with v(k) ~ e(k). such a large v(k) means that the genetic drift would be very large, requiring large i t 's to reduce the drift. it is hence interesting that, even under such stringent conditions, i is still < . in the supplement, we show that the estimated value of i would be substantially lower if we use the poisson distribution of k, associated with the conventional wright-fisher model. with v(k) = e(k), i would be - . hence, the conclusion presented in this section is robust. in the theory of genetic drift [ ] , even a hundred infected travelers from a source viral population would give rise to a fairly uniform level of genetic polymorphism among bordered regions. in contrast, the reported data indicate substantial divergence among countries (gisaid (https://www.gisaid.org/); see supplement). dataset ii of table is realistic in this respect. the divergent polymorphisms across countries depend mainly on a critical parameter -the size of the first cohort arriving in a country, i , which is estimated to be < . the number may in fact be smaller than it seems since a long distance flight carrying one single infected but symptomless patient could infect this many people, all of whom being without symptom upon arrival [ ] . on the robustness of the estimation the model also assumes that each population is an independent sample of the source population. since all populations are likely to exchange some individuals due to travelling, the actual divergence among populations would be even smaller than simulated. in other words, to attain the observed level of divergence, i would have to be even smaller than estimated. considering all these variables, we believe the conclusion of i < to be robust. in the analysis of regional divergence, the results would depend strongly on the smaller i of the two regions being compared. hence, the assumption of the same i among all regions would be a reasonable one. while our focus is on the divergence in the first few generations, we now briefly discuss the subsequent evolution after this initial critical period. the primary lineage delineation, the s/l polymorphism defined by two snps [ ] , have many subtypes (see supplement and table s for details). for example, the western european countries including italy, switzerland, germany and belgium are predominantly of the l type with a similar abundance in the l subtype. in contrast, while japan is also predominantly of the l type, it has mainly the l subtype. this contrast suggests that japan may represent an independent sample from the western european samples, which have likely been spreading regionally after the initial seeding. another example is the s and s subtypes, which differentiate between the samples from china and the west coasts of the us. these patterns suggest that, after the initial seeding, each major region or continent has been evolving along an independent path. since the initial seeding may be extremely difficult to prevent, the onus is to suppress the regional spread. the analyses of the subtypes in asia, australia, and various parts of north america would offer additional details of the spread of the virus, as has been done recently [ ] [ ] [ ] [ ] . these details are beyond the scope of this study that focuses on the early stages of the viral spread. the analysis suggests that the covid- epidemic in each region surveyed was likely started by a very small number of travelers [i < ]. with such a tiny trickle of human movement, it would have been very inefficient for any region to prevent infected individuals from exporting an epidemic to (or importing it from) other places. for that reason, the crucial stage of repressing an epidemic in any region should be the very first sign of local contagion. finally, due to the "portability" of covid- , each epidemic, including the first one on record, could have easily been imported. where then did all these epidemics begin? while the interest in the "origin" is intense, we suggest the question be broadened as 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and its application to the evolution of cell populations the mathematics of infectious diseases modeling the epidemic dynamics and control of covid- outbreak in china reproduction numbers of infectious disease models perspectives on the basic reproductive ratio moral imperative for immediate release of -ncov sequence data on the origin and continuing evolution of sars-cov- the average number of generations until fixation of a mutant gene in a finite population the neutral theory of molecular evolution an introduction to population genetics theory molecular evolution random processes in genetics virological assessment of hospitalized patients with covid- principles of population genetics origins of power-law degree distribution in the heterogeneity of human activity in social networks human behavior and the principle of least effort the reproductive number of covid- is higher compared to sars coronavirus quantifying sars-cov- transmission suggests epidemic control with digital contact tracing transmission interval estimates suggest pre-symptomatic spread of global initiative on sharing all influenza data -from vision to reality substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov- ) evolution and molecular characteristics of sars-cov- genome coast-to-coast spread of sars-cov- during the early epidemic in the united states introductions and early spread of sars-cov- in the new york city structural variation during dog domestication: insights from gray wolf and dhole genomes structural variation provides novel insights into dog domestication speciation with gene flow via cycles of isolation and migration: insights from multiple mangrove taxa we thank all those who have contributed sequences to the gisaid (global initiative on sharing all influenza data) database (https://www.gisaid.org/). acknowledgements and detailed information of the genome sequences we consulted for this study are given in table s . the actual data fitted to our model were computationally generated (see the main text). we thank drs. yaping zhang, suhua shi, weiwei zhai, jianzhi george zhang, bingjie chen, zheng hu and jindong zhao for comments on and suggestions for this manuscript. the authors declare no competing interest. key: cord- -jtr wi c authors: psy, david lazzari; bottaccioli, anna giulia; bottaccioli, francesco title: letter to the editor: kim, s-w., su, k-p. ( ) using psychoneuroimmunity against covid- , brain, behavior, and immunity ( ), doi: https://doi.org/ . /j.bbi. . . date: - - journal: brain behav immun doi: . /j.bbi. . . sha: doc_id: cord_uid: jtr wi c nan we read the recent article by kim & su with great interest. this article was strongly focused on the importance of psycho-neuro-immune networks in the fight against the ongoing pandemic caused by sars-cov- . several crucial aspects of the covid- pandemic were highlighted, including the impact of the pandemic on the populations of the world's richest and most technologically advanced nations, which are experiencing unprecedented conditions of widespread mortality, fear, and social isolation. a recent survey conducted on the italian population during the pandemic showed there is a widespread state of psychological distress among them (i.e. anxiety, depression, sleep disorders and more) , as confirmed in other survey involving three europe countries: italy, spain and united kingdom (see tab. ). the latter survey shows higher level of depression in italian population than the former, probably due to the more specific investigation methods. moreover, predictive analyses showed that mental health of a large proportion of the population in italy, united kingdom and spain is at high risk for stress, anxiety and depression ( %, % and % respectively), due to socio-economic vulnerability and worsened conditions since the pandemic onset (open evidence, ). we believe that this mental condition could plausibly weaken the resistance of individuals and the population to sars-cov- infection. in these conditions of uncertainty, prevention strategies and early intervention for infected patients in primary care settings appear to be crucial for tackling the pandemic. this requires a profound change in our approach to the prevention and treatment of the infection, based on the integration of the biomedical and psychological sciences and professions to promote resilience in the general population. the vast majority of the population appears to actually possess the endogenous resources needed to fight infection by sars-cov- , especially when the infection is silent or occurs with few symptoms. we believe that a rational approach based on psychoneuroendocrineimmunology (pnei), the paradigm built on the two-way relationship between the psychological and biological systems in environmental and social contexts (ader, ; bottaccioli & bottaccioli, ) , could provide an appropriate model for the identification of risk and resilience factors in the context of sars-cov- infection. the pnei model could also help provide a comprehensive understanding of the effects of infection on the whole health status of patients, including their mental state and psychopathological disturbances (bottaccioli et al., ) . a balanced immune response to sars-cov- infection is the central target of efforts to promote resistance and resilience to infection. a number of factors can regulate or unbalance the immune system's antiviral response, including diet, physical activity, stress, and mental state. the clinical features of critically ill covid- patients include widespread malnutrition. malnourished covid- patients in intensive care and sub-intensive care are associated with higher hospitalisation costs, prolonged stays, and increased mortality. therefore, the early initiation of nutritional therapy is vital, particularly in patients with organ failure and sepsis, and could significantly change the course of the disease even in non-critical patients hospitalised in ordinary wards or treated at home (liang, ) . one of the main effects of forced quarantine during a pandemic is reduced mobility. although all members of the population may suffer from a prolonged period of almost total physical inactivity, the elderly population may, once again, pay the highest price. in the elderly, inactivity rapidly depletes muscle reserves and accelerates bone turnover, promoting sarcopenia; it also worsens respiratory function, alters metabolism, and impairs blood pressure regulation. regular physical activity is also a trophic stimulus for the brain (jiménez-pavón et al., ) . depression can be seen as a form of low-grade inflammation (pariante, ) that is particularly active in the brain circuits involved in adaptive behaviour and processing emotional states. this leads to a pathological condition that is continuously fed by inadequate lifestyle behaviours that, in turn, support the inflammatory state and worsen the patient's psychological state (gialluisi et al., ) . treating distress helps fight inflammation (bower et al., ) and can thus, also be a resource in the fight against the covid- pandemic. however, there is currently widespread difficulty in launching a strategy capable of articulating and integrating psychological intervention into health care and society. this difficulty is due to both the forced priority given to medical assistance emergencies in the first phase and, above all, due to a widespread cultural problem that tends to separate psychological aspects from health-related issues and health interventions in general. a cultural problem that does not seem to concern the italian population which, on the contrary, is very favourable to a greater presence of psychologists in primary care services (i.e. hospitals, nursing homes, social services, family physicians' offices) in order to counteract the covid pandemic effects (piepoli institute, april , data being published). if implemented, the large-scale integration of medicine and psychology would provide a formidable new impetus for improving human health care, even during this threatening time. sample of subjects representative of the italian population. on march , the government of italy extended lockdown to entire country: this has raised the stress index national trend towards the higher scores and it remained high after one month. ** the survey was carried out by the piepoli institute for the national council of the order of psychologists ( april ) on a total sample of individuals representative of the italian population divided by gender. ***the survey was carried out by the open evidence, a spin-off of universitat oberta de catalunya (uoc), realized with the contribution of bdi-schlesinger group and università degli studi di milano, universitat oberta de catalunya, universidad nacional de colombia, università di trento, university of glasgow, on a total sample of . subjects divided by countries involved in the survey. the percentages refer to those who reported to have been depressed in the last days (reference period: from / / to / / ). dass- (depression, anxiety and stress scale - items) and sasrq (stanford acute stress reaction questionnaire) were used to quantify depressive symptoms. psychoneuroendocrineimmunology and science of integrate care. the manual stress and the psyche-brain-immune network in psychiatric diseases based on psychoneuroendocrineimmunology: a concise review mind-body therapies and control of inflammatory biology: a descriptive review clinical and immunologic features in severe and moderate coronavirus disease lifestyle and biological factors influence the relationship between mental health and low-grade inflammation physical exercise as therapy to fight against the mental and physical consequences of covid- quarantine: special focus in older people access: / / ) open evidence . the effects of covid- and lockdown in italy why are depressed patients inflamed? a reflection on years of research on depression, glucocorticoid resistance and inflammation key: cord- - gwb o l authors: silva, monalisa r.; lugão, pedro h. g.; chapiro, grigori title: modeling and simulation of the spatial population dynamics of the aedes aegypti mosquito with an insecticide application date: - - journal: parasit vectors doi: . /s - - - sha: doc_id: cord_uid: gwb o l background: the aedes aegypti mosquito is the primary vector for several diseases. its control requires a better understanding of the mosquitoes’ live cycle, including the spatial dynamics. several models address this issue. however, they rely on many hard to measure parameters. this work presents a model describing the spatial population dynamics of aedes aegypti mosquitoes using partial differential equations (pdes) relying on a few parameters. methods: we show how to estimate model parameter values from the experimental data found in the literature using concepts from dynamical systems, genetic algorithm optimization and partial differential equations. we show that our model reproduces some analytical formulas relating the carrying capacity coefficient to experimentally measurable quantities as the maximum number of mobile female mosquitoes, the maximum number of eggs, or the maximum number of larvae. as an application of the presented methodology, we replicate one field experiment numerically and investigate the effect of different frequencies in the insecticide application in the urban environment. results: the numerical results suggest that the insecticide application has a limited impact on the mosquitoes population and that the optimal application frequency is close to one week. conclusions: models based on partial differential equations provide an efficient tool for simulating mosquitoes’ spatial population dynamics. the reduced model can reproduce such dynamics on a sufficiently large scale. [image: see text] the aedes aegypti (linnaeus, ) mosquito is the main vector that transmits dengue, zika, chikungunya, and yellow fever [ ] . urbanization and international travel are key factors that facilitate the spread of these diseases. the study of the spread of mosquitoes and viruses has important implications for understanding diseases, patterns of hyperendemicity, and disease severity, facilitating the planning of public health actions and vaccine development strategies [ ] . dengue is considered among the vector-borne diseases that have spread most rapidly in the world [ ] . the americas, south-east asia, and western pacific are the most affected regions by the dengue fever [ ] . only the americas region reported , , cases through the year of [ ] . over the past years, this endemic disease grew times, expanding geographically to new countries and, in the current decade, from urban to rural settings [ ] . public policies aiming to control dengue epidemics must necessarily include appropriate strategies for minimizing the mosquito population factor [ ] . some papers address different strategies to control the population of ae. aegypti. for example, using bio-insecticide, larvae-eating fish species, and chemical insecticides [ ] ; through controlling the breeding of mosquitoes in the home environment during the year [ ] ; using genetically modified mosquitoes [ , ] ; or in the prospect of sterile insect technique control [ , ] . there are several approaches to modeling the population dynamics of ae. aegypti. the most common one uses ordinary differential equations (odes) following the seminal work by focks et al. [ , ] . the importance of temperature and precipitation on mosquito population patterns is investigated in [ , ] . authors study the vectorial transmission of diseases using odes based on about eight parameters for each spatial location. it is natural to mix this approach with susceptible, infected, and recovered (sir) models. the authors in [ ] use a system of eight ode equations and approximately fourteen parameters to study the evolution of human infection for chikungunya of in several reunion islands cities. the modeling approach based on odes works with total populations. it can not be used to investigate the spatial dynamics of vectors and related phenomena as terrain topography, different urban areas, etc. for example, some authors [ ] , circumvent this issue by using a combination of odes with the graph theory. different possibility to describe the spatial dynamics of the population of ae. aegypti uses partial differential equations (pdes). this approach is based on the assumption that the vectors' displacement is an erratic movement and consequently can be modeled as mass diffusion. several one-dimensional models using this approach have been presented and studied in [ , , ] . however, for these models, it is not possible to analyze the topography of the terrain, considering issues that are very relevant to mosquito propagation, such as heterogeneity and local climatic conditions. a more realistic two-dimensional model can be seen in [ ] . however, this complex model considers seven phases of the mosquitoes' life cycle and results in a significant number (fifteen) of parameters to be determined. in this sense, the current paper follows the work by yamashita et al. [ ] , aiming to model the spatial dynamics of the mosquitoes population way, making it possible to model it in a realistic urban scenario. moreover, we explain how to obtain all used parameters in an attempt to approach mathematical modeling and biological knowledge. since estimating all parameters can be challenging, this article focuses on a two-dimensional model depending on few parameters and maintaining the mosquito population dynamics' main properties, such as the female mobile population and limited carrying capacity of the aquatic phase. we also present how to obtain most of these parameters from experimental data available in the literature using concepts from dynamical systems, genetic algorithm optimization, and partial differential equations. the modeling presented here addresses biological issues and is applied in a real situation considering a heterogeneous scenario in which it is also possible to calculate the population equilibrium. the described approach is used to investigate the impact of the insecticide application frequency in the mosquitoes population. the paper is organized as follows. "background" section describes the experiments which form the background of this work. "methods and modelling" section presents the modeling, explains all parameters and the methods used to estimate them. the numerical algorithm is also described in this section. "results" section presents the main results and finally in "conclusions" section are some discussions and conclusions. ae. aegypti and ae. albopictus dispersion in an endemic urban dengue area in southeastern brazil was analyzed in [ ] . they fed adult females on rubidium chlorideenriched blood (rbcl) [ ] and measured the dispersal by detecting rb-labeled eggs in ovitraps. although there are some limitations in this technique, such as the tip of the proboscises of all rubidium marked mosquitoes were cut off, possibly changing their dispersion [ ] . in general, works addressing mosquitoes dispersion distances [ ] [ ] [ ] measures the maximum value of such dispersion, making it difficult to evaluate the small distance displacement, which is the norm in mosquito biology [ , ] . the described experimental results, in our opinion, are more related to diffusion phenomena (connected to the laplacian operator) then to advection phenomena (modeled as wave propagation). as will be explained in the following sections, it allows us to consider a significant amount of mosquitoes ( % in the current approach) stay in a specific area while the outliers travel further. the release point at [ ] was the center of a circle with a radius of (m). according to [ ] , two weeks before the release of rb-tagged mosquitoes, all houses (about , ) located in the , (m) diameter study area were inspected for containers containing immature mosquitoes that were identified and counted. to evenly distribute the ovitraps, the (m) radius circular area was divided into five concentric areas of - (m) radius ( ovitraps), - (m) ( ovitraps), - (m) ( ), - (m) ( ) and - (m) ( ), respectively, similar to fig. , [ ] . in this way, the number of ovitraps per square meter is approximately the same in the investigated area. dispersal of ae. aegypti-fifty-one ovitraps ( on day and on day ) were found with rb-marked ae. aegypti eggs, table . ae. aegypti rb-marked eggs were found up to (m) from the release point. none of the ovitraps placed up to (m) from the release point was positive for rb-marked ae. aegypti eggs. we consider four main phases in the life cycle of the ae. aegypti: the mobile female in the reproductive phase (transmits diseases), the egg phase (substantially increases the mosquito population), larva and pupae phases (in this paper we join them into the aquatic phase for simplicity). for simplicity, in this mosquitoes' population dynamics model, we consider larva and pupae as one phase, see fig. . we are interested in an urban spatial scale, where diffusion represents the dispersion of the mosquitoes due to the autonomous and random movements of the winged females. variables m, a, and e represent the population density of ae. aegypti mosquitoes in the mobile, aquatic, and egg phases, respectively. coefficients µ and µ represent the mortality of the mobile and aquatic phases respectively; k is the carrying capacity for the aquatic phase; r represents the oviposition rate of females; d is the diffusion coefficient of females; γ is the immobile phase maturation rate; e is the hatching rate. due to the very high resistance of the egg phase (up to days [ ] ), as we are interested in an urban spatial macro-scale modeling, we do not consider the mortality in the egg phase. quantitatively the results presented in this paper do not change significantly considering such parameter. the model is described by the following system of partial differential equations: where the domain of variables m(x, y, t), e(x, y, t), a(x, y, t) and initial conditions inside some spatial domain ⊂ r are given by system ( )-( ) can be regarded as a modification of the model presented in [ ] , neglecting the term referring ≤ a(x, y, t) ≤ k, a(x, y, ) = a (x, y). convection and dividing the immobile phase into an aquatic phase (larvae and pupae) and an egg phase. this model can also be regarded as a modification of one presented in [ , ] , where we separate eggs from the aquatic phase and consider only the mobile female population. the carrying capacity, based in [ , ] , represents a space limitation of one phase due to situations present in the environment, such as competition for food among the larvae [ ] . the carrying capacity was neglected in the egg phase because of the skip oviposition phenomenon [ ] . limitations in the winged phase were not reported in any study. finally, we consider the limitation term in the aquatic phase (larvae and pupae), where it is effective [ ] . . as the term ∇ · (d∇m) can not change the sign of m, when m is approaching zero, the right side ( ) is not negative. . the right side of ( ) remains positive, when the initial conditions (m , e , a )(x, y) are inside the domains definition, the solution of ( )-( ) remains inside this domain. . when a approaches zero the right side of ( ) is not negative. when a approaches k (from below) the first term in the right side of ( ) tends to zero, while the second term remains negative. the time elapsed from the hatching of the larvae to the emergency of the pupae in the adult phase can be measured experimentally. for example, [ ] reports approximately eight days of maturation at a fixed temperature of • c. to estimate a maturation rate coefficient γ from this value, we divide per the maturation time taking into account / ratio of male/female. the result is γ = . female mosquitoes per day. for the oviposition rate, we need to measure the number of eggs per day deposited by a single mosquito. in this case, we use the experimental data from [ ] , that reports an average of . eggs per day during five days of the oviposition period at • c with % relative humidity. it corresponds to . eggs in the total lifetime of eleven days seen in the experiment. as the oviposition rate corresponds to an average egg deposition during the mosquitoes' lifetime, we divide the total number of eggs per lifetime to roughly estimate r = (eggs/day). we assume that all eggs hatch and the corresponding mortality rate coefficient is equal to zero. the mortality rate coefficient of the aquatic phase is defined by the larvae's coefficient, resulting in the parameter µ approximately equal to . ( /day) [ ] . the mobile phase mortality rate coefficient is calculated as a sum of the base mortality rate and an increment due to insecticides impact: considering both natural death and accidental ones, approximately % of mosquitoes in the adult phase dies at each day [ ] , giving us a base mortality rate coefficient in order to model the mortality rate increment due to insecticide impact on the mosquitoes' population, we add a correction factor to the base mortality rate. to model this factor we consider the eq. ( ) neglecting diffusion term, maturation term, and also neglecting the base mortality rate ( µ = µ i ): this type of equation appears in many applications. in particular, for chemical reactions, the characteristic time (time corresponding to complete the major part of the reaction) is defined as t char = /µ [ ] . we consider the insecticide effect of being minutes, which is the time insecticide suspension stays in the air [ ] . taking this value as a characteristic time, we arrive at the reference value of the mortality rate of µ i in what follows, we considered the same application time of minutes for all insecticide application frequencies. the characteristic time for different mortality rates considered in this paper are presented in table . the focus of the model application addressed in this paper is to investigate the impact of the insecticide application frequency in mosquitoes' population. thus the total amount of insecticide applied is the same, making it possible to compare different application strategies. for example, if applied every two weeks, the mortality correction factor is µ i = ( /day) for thirty minutes; when applied once a week, the mortality correction factor is by µ i = ( /day) for thirty minutes and so on. while the diffusion coefficient is the most important parameter to define the mosquitoes' displacement, it cannot be easily estimated from biological aspects as the previous parameters. we use the experimental data [ ] to estimate its value through two different approaches: analytical and numerically using the heuristic method. in order to replicate the experiment, the model was simplified: since the focus of the experiment is the dispersal of the initially released rb-tagged mosquitoes during a short period, the immobile phase equation is neglected. therefore, the model is simplified to: with the initial condition m(x, y, ) = m · δ(x, y) , where δ(x, y) is a dirac delta function, and m the number of mosquitoes released in the center of the circle. equation ( ) possesses analytical solution for the unbounded two-dimensional domain: as this solution decays exponentially with the distance from the origin, considering a sufficiently large domain, the difference from this solution and the correct solution for limited domain on the boundary is negligible. thus we can use it to estimate mosquitoes distribution. the analytical approach presented in this paragraph is only used to obtain the diffusion coefficient from the experimental data [ ] . notice that the authors in [ ] do not apply insecticides and that the total experiment duration was days. during such a short period, the mosquitoes' mortality does not impact results significantly. besides, this analytical solution is used to validate the heuristic approach (presented next), which fits diffusion and mortality coefficients. we use the solution ( ) without the mortality term ( µ = ) and integrate it to find the diffusion coefficient d, such that in seven days % of the initial population is within the circle of radius (m). while these values seem arbitrary at first, the experiment in [ ] shows us that (m) is a minimum radius to consider since mosquitoes can be found in all the explored area. the authors in [ ] also corroborate this remark stating that in dry seasons, like the one where the experiment takes place, the mosquitoes can be found at a maximum distance of (m) from the release point. for the heuristic approach, the experimental data are compared to the simulated one with the following methodology. first, the solution ( ) with to-be-fitted values d, and µ is obtained within each of the areas analyzed by the experiment. each integral value is multiplied by a constant parameter α , which indicates the probability of mosquitoes to lay eggs into the ovitraps in the investigated area. the resulting values r are compared to the experimental data e. a genetic algorithm, described in "genetic algorithm" section, is used to fit d, µ , and α, minimizing the error between r and e. the carrying capacity depends on external factors such as food availability, climate factors, terrain properties, making a direct estimation almost impossible. in order to estimate the carrying capacity coefficient k, we extend the methodology presented in [ , ] . let χ ∈ r be a part of the domain, where the variables m, a, and e can be considered homogeneous. this assumption agrees with the experimental data, where there is always a limited number of traps. for example, the region χ can be a block, a neighborhood, or a town. considering a compact χ with smooth boundary Ŵ , and assuming a sufficiently smooth solution m, gauss's theorem results in: where n is a normal vector pointing outwards the region χ . for simplicity let us consider that χ is isolated from the neighbor regions. thus, to estimate carrying capacity coefficient, it was considered that there are no mosquitoes entering or leaving χ resulting in ∇m · n = in Ŵ. under the discussed hypotheses, integrating system ( )-( ) in χ and dividing the resulting equations by the area of χ , yields the following system of ordinary differential equations: systems similar to ( ) were studied in the literature [ , , , ] . the solution is the traveling wave connecting two equilibria (m, e, a) = ( , , ) and (m, e, a) = (m * , e * , a * ) , where the second one corresponds to the maximum number of mosquitoes. we assume this behavior here as the proof stays outside of the scope of this paper. equating the right side of system ( ) to zero results in: where: is equivalent to the basic offspring number [ ] . it can be noted that there is a bifurcation here. when q ≤ the only valid equilibrium inside the variables' definition domain ( ) is ( , , ), since m * , e * and a * are non positive. if q > , values < m * , < e * , and < a * < k . for more details see [ ] . different experiments obtain the number of eggs, or larvae, or female and male mosquitoes. for example, the authors in [ , ] collected the number of ovitraps in which the females laid eggs in a determined evaluated region. another work [ ] shows the spatial distribution of ae. aegypti and ae. albopictus larval densities. the authors in [ ] investigates the concentration of ae. aegypti females. in this way, using the eqs. ( )- ( ) allows estimating the presented models carrying capacity coefficient for all these cases. in this work, we obtain a value of the carrying capacity coefficient k from the adult mosquitoes estimated population found in [ ] . one of its experiments in an urban neighborhood report approximately mosquitoes in a region of ( m ), corresponding to m * ≈ . ( #/m ) mosquitoes. the final expression for k is computed using this value for m * . the experimental data [ ] suggests that, in optimal conditions of humidity, the mean value of the hatching rate coefficient is . ( /day) with a temperature of ( • c ), which is considered ideal for the development of the mosquito. in this model, we consider the value e = . ( /day), even though it is known that this parameter is highly dependant on climatic conditions. in this section, we briefly describe numerical methods used in this paper. a simple genetic algorithm is used to fit the parameters by minimizing the error between the experimental data [ ] and the simplified model described in "how to estimate diffusion coefficient" section. the finite volume method (fvm) is used to simulate the model ( )-( ). this sections goal is to fit parameter values of d, µ and α by minimizing the error function the set of different weights w i for each region w = ( , , , , ) is used to give more attention to the radial propagation of the mosquitoes. the structure of a genetic algorithm is described in algorithm , see [ ] for more details. in the algorithm , the selection function, used to choose the best parent candidates and the next generation is given by tournaments of size , i.e., between four possible candidates and select the one with minimal error function. the crossover uses an arithmetic function, where the new candidate has the average values between two parents. the solutions are bounded, and the adaptive feasible mutation function ensures that the mutated candidates stay in the defined bounds. note that the bounds used in the optimization help to achieve a more realistic local minimum of the problem. for the boundaries we consider that the parameters must be positive, d is limited in ( m /day), µ is lower than ( /day) and the upper bound for α is estimated to be less than . because of the considered number of released mosquitoes ( m = ) and the data collected by the experiment. the governing equations describing the population dynamics of ae. aegypti have been discretized using an explicit fvm [ ] considering ω ij as a cell centered in (x i , y j ) , we solve each integral separately. for the left side of the system ( )- ( ) , taking m, e or a as u, it follows: y j+ / y j− / we have x = x i+ − x i = y j+ − y j = y defined by the uniform discretization of the spatial grid, and t = t n+ − t n is the time step used in the temporal evolution of the solution. for the second term in ( ) (diffusion term), first consider the derivative only in the x direction: using a similar calculation for the y direction and adding both equations for x and y directions we obtain the second term in ( ) (diffusion term). for simplicity we denote this term d(m n ij ). the integral of each source term is approximated as follows: substituting the integrals into ( )-( ) leads to following system: using a crank-nicolson discretization for the right side of ( )- ( ) and rewriting the equations in terms of the previous time and the next time, it follows the implicit scheme: ( ) y j+ / y j− / the simulation consists in solving the nonlinear system ( )- ( ) for m n+ , e n+ and a n+ at each time step to calculate the population distribution of each phase. we use a time step lower or equal to thirty minutes. more details on this method can be found in [ ] [ ] [ ] . for the simulations, we consider the area highlighted by a rectangle in fig. . figure shows the corresponding computational domain, where yellow color indicates the area affected by the insecticide, and blue color indicates the house blocks. notice that the yellow area is slightly larger than the streets because of the diffusion effect of the insecticide pulverized in the air. the simulations were performed using finite volume method explained in "finite volume method" section with initial conditions m ij = . ( /m ) and . parameter values are in table . we run the simulations for two scenarios explained next. heterogeneous scenario it considers that diffusion coefficient value inside house blocks is equal to half of that obtained in "parameter estimation" section, since streets are more favorable place for mosquitoes movement. mortality coefficients inside home blocks are also considered to be % of those in streets since there are more natural conditions contributing to mosquitoes' mortality outside houses, see table . the considered spatial variation of the parameters are hypotheses made by the authors only to show how the model deals with a heterogeneous scenario. despite being close to fitted values or to values obtained from literature, the exact multipliers corresponding to each city area could not be determined. the average diffusion and average mortality coefficients were maintained equal in heterogeneous and homogeneous scenarios to enable the comparison between both. homogeneous scenario it considers that the diffusion and mortality rates of mosquitoes are equal in streets and inside house blocks. corresponding parameter data for d, µ and µ are in table . the importance of this simplified case is that it allows us to make a bridge with the ode theory, which results are presented in "how to estimate carrying capacity coefficient" section. in order to compare homogeneous and heterogeneous scenarios parameters d, µ and µ were calculated as a weighted average between the parameters of streets and houses ( ) proportional to the area of the respective environment, see table . this section aims to describe the results obtained by the previously described methodologies. "parameter estimation" section focuses on the parameter estimation using both the genetic algorithm and the analytical approach. "population dynamics simulation and validation" section shows results comparing the numerical solution to the experimental data and the analytical solution of the model. simulation results for the complete model with the fitted parameters are also presented. given the random nature of the genetic algorithm, it was executed in a -fold scheme, calculating the mean value of each parameter, and its standard deviation. the resulting mean and standard deviation are presented in table . the relatively low standard deviation indicates that the results are close to the same local minimum in the limited search space. due to the experiment's short duration, eq. ( ) is simplified by removing the mortality term resulting in a heat equation, which possesses a well known analytical solution. considering initial data given by the dirac function and using heat kernel [ , p. ] the two-dimensional solution is given by: where σ (t, d) = √ dt is the standard deviation, that also represents the "gaussian width" of the kernel function. we search for the parameter d, such that % of the initial mosquitoes population stays inside the circle of radius (m) after seven days of the experiment. for all normal distributions, approximately % of the area is within . standard deviations of the mean value, in this case zero. we substitute the values in . σ ( , d) = (m), yielding d = (m /day). in this subsection, we present the numerical results of the direct simulations using fvm. initially, we perform a simulation in a d homogeneous domain using a simplified model given by eq. ( ) . for this simulation, we use parameter values of d and µ obtained in previous sections and summarized in table . integrating the numerical solution at t = (days) on each of the areas described in fig. and multiplying the results by the probability of detecting mosquitoes in the trap α = . gives us values to compare with the experimental data, as seen in the fourth column of table . the analytical results in table (third column) are obtained using same parameters in the eq. ( ) and performing the same integration multiplied by α. figure presents mobile phase population density distribution obtained from the simulation of the heterogeneous scenario for weekly insecticide application, see table . notice that each sub-figure uses its color scale for better understanding. as can be observed in fig. , there are bigger blocks in the center of the considered neighborhood. figure a shows that, as expected, bigger blocks offer more conditions for the proliferation of the vector. figure b shows that, immediately after the insecticide application, the population density in the streets decreased considerably, while the population inside small blocks is more affected than in bigger blocks. these results are reasonable since pulverized insecticide can not reach areas more distant from the streets. figures c, d show the population recovery after the application of the insecticides. it is clear than the bigger blocks are the source of such recuperation allowed by the presence of the egg and aquatic phases. we compare different insecticide application strategies by calculating the integral of the population density in the entire region at each time step. figures and show total mosquitoes' population at each day for the homogeneous and the heterogeneous scenarios, respectively. both figures show five simulations: four simulations with different application strategies (see table ) and the case without insecticides use for comparison. the methodology presented in "how to estimate carrying capacity coefficient" section allows us to calculate an equilibrium state for total mobile mosquitoes' population using eq. ( ) . in the homogeneous scenario without insecticides, we use eq. ( ) directly. to deal with heterogeneous parameters, we apply eq. ( ) to each grid point to find a local equilibrium, and then we sum the results for all grid points to obtain a total population equilibrium. to deal with discontinuous insecticide application, we consider the mortality coefficient (e.g., ( /day)) and divide it by the number of half-hour periods in the corresponding time (in this case ), simulating the effect of the same insecticide concentration applied continuously. the resulting equilibrium solutions are plotted in figs. and . as one can see, formula ( ) gives perfect a match for equilibrium solution and no insecticide case in both scenarios. when insecticides are applied, the total mobile mosquitoes' population oscillates close and below the equilibrium solution in both scenarios. in this case, the total mobile population approximates the equilibrium value given by eq. ( ) when applications become more frequent. one of the goals aimed by the present article is to evidence the possibility of describing mosquitoes' spatial population dynamics through a model with few parameters. we presented model simulations using the limited and discrete computational domain using a twodimensional step function for the spatial variation of the parameters in the heterogeneous scenario. the temporal dependency of parameters is neglected. this simplicity is essential since complex models that rely on a large number of parameters can frequently present limited applications as these parameters are almost impossible to obtain. numerical fitting of a large number of parameters and limited data inevitably raises the question of a local minimum problem. in our opinion, the spatial dynamics of mosquitoes' population can be modeled using a diffusion equation. for the mathematical model cited above, we present how to estimate the main parameter values (diffusion coefficient, mortality rate, and carrying capacity) from the literature [ , ] . in particular, for the diffusion coefficient, the values obtained through analytical estimates using the heat equation and the numerical fitting through genetic algorithm are close to values found in the literature, evidencing the robustness of the method. we hope the presented methodology will facilitate real applications of these types of models in public health strategies planning. equations ( )- ( ) allow two applications in the mosquitoes' population dynamics modeling. firstly, given experimental data on a maximum number of mobile female mosquitoes or the maximum number of eggs or the maximum number of larvae, they allow the estimate of the carrying capacity of the larvae phase. this coefficient, presented in many models, is almost impossible to estimate otherwise. secondly, if one knows the carrying capacity coefficient, eqs. ( )-( ) allow calculating an equilibrium solution for these three phases. our simulations show that this equilibrium solution is an over-bound for the oscillating mosquitoes' mobile phase population, even in scenarios when mobility and mortality coefficients are considered different between house blocks and streets. in this case, assuming a direct correlation between the number of mosquitoes and the number of contaminated people, this simple algebraic formula allows us to estimate the effect a given insecticide application strategy will have on public health. numerical simulations show that the increased frequency of insecticide application does not imply the fig. heterogeneous scenario -total population of mobile phase by time with different application strategies. dotted lines represent equilibria found by eq. ( ) decrease of mosquitoes' population. in fact, more spaced applications lead to bigger oscillations, as can be observed in figs. and . quantitatively these oscillations are shown in table . notice that the lower average population corresponds to the weekly application. simulations of the heterogeneous (more realistic) scenario show that mosquitoes' main population remains inside house blocks and is not accessible to insecticides application. these places work as a source for a fast mosquitoes' dissemination and population recovery. taking these results into account together with the damage insecticides cause to other insect species [ ] should incentive the debate over the application of this control technique. better planning optimizes the insecticide application and can diminish such damage. finally, it is important to state that more precise results need correct mortality coefficients, which can be obtained through specific experiments. in conclusion, our results show the following. • the simple modeling based on diffusion properties showed satisfactory results for describing the mosquitoes' spatial population dynamics in the heterogeneous urban environment. • the total population equilibrium is affected by insecticides' application, and the periodicity of application plays a significant role in the average total mosquitoes' population. • considering the limitations in data (all parameters are fitted or obtained from the literature) and modeling, our results suggest that the weekly insecticide application results in a local minimum of the average mosquitoes' population. however, more research needs to be done to determine the optimal strategy for vector control. chikungunya and dengue: the causes and threats of new and re-emerging arboviral diseases global spread of dengue virus types: mapping the year history world health organization. global strategy for dengue prevention and control - . geneva: world health organization world health organization: weekly epidemiological record. weekly epidemiological record relevé épidémiologique hebdomadaire paho: epidemiological update dengue jatropha curcas l. 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impact of small variations in temperature and humidity on the reproductive activity and survival of aedes aegypti (diptera, culicidae) aedes aegypti: biology and ecology department of health-new york state: information sheet: malathion and mosquito control biologia e comportamento do vetor. dengue: teorias e práticas assessment of a trap based aedes aegypti surveillance program using mathematical modeling propagação da dengue entre cidades assessing the effects of temperature on the population of aedes aegypti, the vector of dengue chiaravalloti neto f. study of the relationship between aedes (stegomyia) aegypti egg and adult densities, dengue fever and climate in mirassol, state of são paulo, brazil the spatial distribution of aedes aegypti and aedes albopictus in a transition zone estimating the size of aedes aegypti populations from dengue incidence data: implications for the risk of yellow fever outbreaks introduction to evolutionary computing finite volume methods for hyperbolic problems finite volume method for radiation heat transfer numerical heat transfer and fluid flow mosquito-borne diseases, pesticides used for mosquito control, and development of resistance to insecticides publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to thank fábio prezoto and samuel lima for their assistance with the biological phenomenon. mrs: formal analysis, investigation, writing-original draft, writing-review and editing. pgl: software, formal analysis, investigation, writing-original draft, writing-review and editing. gc: conceptualization, supervision, formal analysis, investigation, writing-original draft, writing-review and editing. all authors read and approved the final manuscript. this study was financed in part by the coordenação de aperfeiçoamento de pessoal de nível superior -brasil (capes) -finance code . g.c. was supported in part by cnpq grant / - . not applicable. not applicable. not applicable. the authors declare that they have no competing interests. key: cord- -qvuv g authors: amster, guy; murphy, david a.; milligan, william m.; sella, guy title: changes in life history and population size can explain relative neutral diversity levels on x and autosomes in extant human populations date: - - journal: biorxiv doi: . / sha: doc_id: cord_uid: qvuv g in human populations, relative levels of neutral polymorphism on the x and autosomes differ markedly from each other and from the naive theoretical expectation of ¾. these differences have attracted considerable attention, with studies highlighting several potential causes, including male biased mutation and reproductive variance, historical changes in population size, and selection at linked loci. we revisit this question in light of our new theory about the effects of life history and given pedigree-based estimates of the dependence of human mutation rates on sex and age. we demonstrate that life history effects, particularly higher generation times in males than females, likely had multiple effects on human x-to-autosomes (x:a) polymorphism ratios, through the extent of male mutation bias, the equilibrium x:a ratios of effective population sizes, and differential responses to changes in population size. we also show that the standard approach of using divergence between species to correct for the male bias in mutation results in biased estimates of x:a effective population size ratios. we obtain alternative estimates using pedigree-based estimates of the male mutation bias, which reveal x:a ratios of effective population sizes to be considerably greater than previously appreciated. we then show that the joint effects of historical changes in life history and population size can explain x:a polymorphism ratios in extant human populations. our results suggest that ancestral human populations were highly polygynous; that non-african populations experienced a substantial reduction in polygyny and/or increase in male-biased generation times around the out of africa bottleneck; and that extant diversity levels were affected by fairly recent changes in sex-specific life history. significance statement all else being equal, the ratio of diversity levels on x and autosomes at selectively neutral sites should mirror the ratio of their numbers in the population and thus equal ¾. in reality, the ratios observed across human populations differ markedly from ¾ and from each other. because from a population perspective, autosomes spend an equal number of generations in both sexes while the x spends twice as many generations in females, these departures from the naïve expectations likely reflect differences between male and female life histories and their effects on mutation processes. indeed, we show that the ratios observed across human populations can be explained by demographic history, assuming plausible, sex-specific mutation rates, generation times and reproductive variances. neutral polymorphism patterns on the x and autosomes reflect a combination of evolutionary forces. everything else being equal, the x to autosome (x:a) polymorphism ratio should be ¾, because the number of x-chromosomes in a population is ¾ that of autosomes. a complication, however, is that autosomes spend an equal number of generations in diploid form in both sexes, whereas the x spends twice as many generations in diploid form in females as in haploid form in males. as a result, the x:a polymorphism ratio can also be shaped by differences in male and female life history and mutation processes, as well as by differences in the effects of demographic history and selection at linked sites on the x and autosomes. the effects of these factors have been studied theoretically ( ) and in relation to observations in many species ( ) ( ) ( ) ( ) ( ) ( ) . notably, their effects on polymorphism ratios in human populations has garnered considerable interest over the past decade ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the impact of selection at linked sites on neutral diversity levels could differ for x and autosomes because of differences in recombination rates, in the density of selected regions, and in the efficacy and modes of selection. notably, the hemizygosity of the x in males leads to a more rapid fixation of recessive or partially recessive beneficial alleles and to a more rapid purging of recessive deleterious ones ( , ) . accounting for these effects and for recombination rates suggests that in humans-in mammals more generally-the effects of selection at linked sites should be stronger on the x ( ( ) , but see ( ) ). to evaluate these effects empirically, several studies have examined how polymorphism levels on the x and autosomes vary with genetic distance from putatively selected regions, e.g., from coding and conserved non-coding regions ( , , , ( ) ( ) ( ) . in most hominids, including humans, such comparisons confirm the theoretical expectation that selection at linked loci reduces x:a ratios ( , , ) . they further suggest that the effects are minimal sufficiently far from genes ( , ) , thereby providing an opportunity to examine the effects of other factors shaping x:a ratios in isolation, by considering regions that are minimally affected. even far from genes, however, the x:a ratios in humans and other hominids differ markedly from the naive expectation ( , , ) . polymorphism levels on the x and autosomes are typically divided by divergence from an outgroup (e.g., divergence to orangutan or rhesus macaque is used to normalize polymorphism levels in humans) in order to control for the effects of higher mutation rates in males and variation in mutation rates along the genome ( ) . the normalized estimates of x:a ratios in regions far from genes range between ¾ and among human populations, generally decreasing with the distance from africa ( , , , ) . ratios exceeding ¾ have also been observed in most other hominids ( ( ), but see ( )). these departures from ¾ and differences among populations and species have been attributed in part to the effects of demographic history, in particular to historical changes in population size. if we assume that the effective population size on the x is generally smaller than on autosomes, then changes in population size will have a different impact on polymorphism levels on x and autosomes ( , ( ) ( ) ( ) . notably, population bottlenecks that occurred sufficiently recently, such as the out of africa (ooa) bottleneck in human evolution, will have decreased the x:a ratio, because a greater proportion of x-linked lineages will have coalesced during the bottleneck ( ) . indeed, simulation studies suggested that historical changes in population size have contributed substantially to the x:a ratios decrease with the distance from africa ( ) . historical differences between males and females may have also played a role. for example, keinan and colleagues speculated that male biased migration or longer male generation times during the out-of-africa bottleneck contributed to the lower x:a ratios in non-africans ( ) . sex differences in life history traits are also likely to have had substantial effects on x:a ratios. the most straightforward of these effects arises from higher reproductive variances in males than in females (e.g., due to sexual selection ( )), which cause higher coalescence rates on autosomes and thus increased x:a ratios ( , ) . this increase is theoretically bound by a multiplicative factor of # ( ), but is probably much smaller in reality. nonetheless, greater male reproductive variances in extant hunter-gatherers and hominid species ( ) , suggest that male biased variance plausibly contributed to observed differences in x:a ratios, as well as to their departure from # . in addition, higher generation times in males may have also had substantial yet underappreciated effects ( ) . higher generation times in males decrease coalescence rates on autosomes compared to the x and thus the x:a ratio of effective population sizes ( ) . in addition, mutation rates in humans-likely in mammals more generally-increase more rapidly with paternal than with maternal age ( ) ( ) ( ) ( ) ( ) ( ) . longer generation times in males therefore decrease mutation rates on the x relative to autosomes. normalizing polymorphism estimates by divergence to an outgroup may not fully account for this mutational effect if, as is likely, male mutation bias evolve over phylogenetic time scales ( ) ( ) ( ) ; moreover, normalized ratios also reflect a non-mutational generation times effect on x:a divergence ratios, as longer generation times in males imply fewer generations on autosomes relative to the x since the species split ( , ) . thus, male and female generation times can in principle affect x:a ratios in multiple ways, which should be considered jointly. here we examine these effects, and those of life history more generally, on polymorphism ratios in humans. we begin with general considerations: about the effects in populations of constant size, about the effects in response to changes in population size, and about biases introduced by normalizing polymorphism ratios by divergence to an outgroup. we then estimate x:a polymorphism ratios in six human populations in which historical changes in population size were inferred previously, and show that considering these effects jointly can explain the observed ratios. life history effects in populations of constant size. in a parallel paper ( ) , we derive expressions for neutral x:a polymorphism ratios in a panmictic population of constant size, under a model that captures quite general life history effects. the model assumes that the population is divided into sex specific age classes, with female and male proportions % and & at birth, respectively ( % + & = ), and that the sizes of subsequent age classes of each sex declines with age, reflecting sex and age specific mortality. fecundity also depends on sex and age and incorporates sex-specific reproductive variances and correlations in the numbers of offspring at different ages. generation times in females, % , and in males, & , are defined as the expectations of maternal and paternal ages. mutation rates can vary with sex and age, with their per generation rates in females, % , and in males, & , defined as expectations over parental ages. the expected numbers of offspring of each sex necessarily equals , but female and male reproductive variances, % and & respectively, may differ due to sex and age dependent mortality and fecundity. we show that the x:a ratio of effective population sizes is then: where ( ) = bcde fcdf . here we define the effective population sizes such that they equal the number of individuals under the standard wright-fisher model, but we note that they are sometimes defined as the inverse of coalescence rates (e.g., in the statement that all else being equal, the x:a ratio of . is ¾). we refer to the x:a ratio of inverse coalescence rates as the genealogical ratio, which in this case is simply ¾ times the ratio of . values. we also show that the x:a ratio of expected heterozygosities is females and males at birth in humans are nearly equal, we henceforth assume that they are, and thus that the latter ratio equals ( + & )/( + % ); for brevity, we refer to it as the ratio of reproductive variances. all three ratios in eq. are male-biased in many taxa ( ) ( ) ( ) . we examine their effects on x:a polymorphism ratios in humans, given available estimates. sex-specific reproductive variances were measured in five extant hunter-gatherer groups, albeit using small sample sizes, and found to be . - . folds higher in males ( ) , with reproductive variances ratios corresponding to a - % increase in x:a polymorphism ratios. sex-specific generation times were measured in seven hunter-gatherer groups, with mean generation times found to vary between and years and generation times ratios between . and . ( , ) , corresponding to a . %- . % decrease in x:a polymorphism ratios. male mutation bias, , was estimated in pedigree studies ( ) , and found to increase approximately linearly on the sex- normalizing ratios of polymorphism using divergence. most studies estimate x:a genealogical ratios by dividing polymorphism levels by estimates of the number of substitutions since the split from an outgroup (e.g., ( , , , ) ). this "normalization" is meant to control for differences in mutation rates on the x and autosomes, due to male mutation bias and differences in base composition. we now ask whether this practice is valid, and in particular whether it controls for male-biased mutation when we account for life history effects on polymorphism and substitution rates. to this end, we rely on eq. for the polymorphism ratio (ignoring changes in population size) and on a parallel expression for the substitution ratio where by '*' we denote parameters averaged over the lineage on which substitutions are measured (the specific form of averaging is detailed in ( )). the second term (on the right-hand side) is the x:a genealogical ratio. the first term (in brackets) includes the mutational effect on the polymorphism ratio and the terms introduced by the normalization. for the normalization to fulfill its purpose of canceling out the effect of male mutation bias, this term should equal . previous work suggests that male mutation bias ( = & % ⁄ ) evolves substantially over phylogenetic time scales ( , ) , and therefore the mutational is unlikely to cancel out. however, even if it did, the dependence of the substitution ratio on the generation times ratio introduces an additional term, ( & * % * ⁄ ). both terms are likely to lead to bias in estimates of the genealogical x:a ratio in a given population. furthermore, as the degree of male mutation bias probably varies among populations (e.g., due to variation in generation times ( ) ), relative estimates of genealogical ratios in different populations will likely biased as well. we can assess the severity of these biases for estimates of human x:a genealogical ratios by comparing divergence-and pedigree-based estimates of the male mutation bias, (fig. ). if differences in the mutation rate between the x and autosome arise predominantly from the male mutation bias (see discussion), then we would expect estimates of the mutational effects on x:a polymorphism ratios based on contemporary pedigree studies to be more reliable. indeed, while mutation rates may have evolved over the period in which neutral diversity in extant human populations arose (e.g., on the order of ~ . my ( ); see discussion), such changes were likely smaller than the changes over phylogenetic time scales (e.g., on the order of ~ and ~ my for divergence from orangutans and rhesus macaques, respectively ( )). second, while both divergence and pedigree-based estimates of depend on the sex ratio of generation times, in pedigree studies, this dependence reflects only the effect of generation times on mutation rates (as opposed to the non-mutational term ( & * % * ⁄ ) for divergence) and is explicit. pedigree-based estimates of , again assuming a linear dependence on & / % ( ) and estimates of & / % in extant hunter-gatherers ( , ) , range between . to . , and estimates in most societies point to the higher end of this range. these estimates are approximately twofold greater than those based on human-orangutan or human-macaque divergence (fig. ) , commonly used to normalize human x:a ratios ( , , , ) . this strongly suggests that current estimates of human x:a genealogical ratios are substantially biased. table s ) and on contemporary pedigree studies (si section ; ( )). pedigree-based estimates strongly depend on, and are therefore shown as a function of, the generation times ratio, & / % . they depend only weakly on the average generation time, , as shown by the (cyan) range corresponding to between - years. revised estimates of human x:a genealogical ratios. we therefore revisit the estimation of genealogical x:a ratios in human populations. we first estimate x:a polymorphism ratios normalized by divergence, in order to correct for local variation in mutation rates on x and autosomes ( ) , and then we rely on pedigree studies to correct for the bias in divergence-based estimates of . we estimate normalized, neutral polymorphism ratios in the absence of selection at linked sites in two ways (si section . ). first, we apply the standard method ( ), based on measuring polymorphism and divergence at putatively neutral sites far from exons. second, rather than imposing a threshold distance from exons, we use sites throughout the genome and rely on the mcvicker et al. b-maps to correct for the effects of selection at linked sites ( ) ; this approach allows us to use more data. our estimates based on the two approaches are consistent (fig. s ) and we henceforth rely on estimates using the second approach (fig. ) , which are more precise. for unclear reasons, they do not agree with the estimates of arbiza et al., which rely on similar data but are slightly higher in yri and much higher in other populations ( ) . to examine how much male-mutation bias affects estimates of x:a genealogical ratios, we assume = . , corresponding to the pedigree based estimate with the average & % ⁄ measured in extant huntergatherers (fig. ) . we then obtain the corrected estimates by multiplying our divergence-normalized estimates by ( . )/ ( \ ] ), where \ ] is the divergence-based estimate of male mutation bias. dividing by ( \ ] ) also removes the potential effect of differential levels of ancestral polymorphism on x and autosomes. the resulting estimates are ~ % greater than those based on divergence alone, suggesting that the genealogical x:a ratios in humans are considerably greater than previously appreciated (fig. ) . as we already noted, pedigree-based estimates of strongly depend on & % ⁄ . since this ratio likely varies over time and among populations, we cannot estimate genealogical x:a ratios that reliably. this limitation is not specific to us, but instead highlights the difficulty of teasing apart the mutational and genealogical effects on x:a polymorphism ratios without making explicit or implicit assumptions about male mutation bias and its evolution. explaining genealogical ratios in human populations. instead, we turn the question on its head and ask whether the effects of sex ratios of generation times and reproductive variances as well as historical changes in population size could explain the estimates of x:a polymorphism ratios that are normalized by divergence. to this end, we rely on pairwise msmc-based estimates of historical, autosomal effective population sizes for the six g populations in which these were inferred ( fig. a; ( ) ). in all cases considered, we assume that = , to match the assumptions of these previous demographic inferences ( ) . we first consider the ratio in yri, then the reduction in ratio in ceu relative to yri, and lastly, the ratios in all six populations jointly. polymorphism ratio in yri. the x:a polymorphism ratio in yri is remarkably high (fig. ) , which is indicative of substantial polygyny (i.e., that a minority of males sired offspring with multiple females). accounting for historical changes in population size and assuming, for example, the average generation trade-off in which assuming a higher generation times ratio implies more extreme male-biased reproductive variances (fig. ) . given that the generation times ratio was likely greater than , our findings suggest substantial polygyny (where a minority of males sire offspring with multiple females) in the ancestors of yri, and thus of other human populations ( ) . ) are constrained to be between and . ; these ranges are somewhat arbitrary, yet they are clearly possible, given estimates in extant hunter-gatherers ( ) . requiring the ratios to have been the same in both populations and constant over time (model ii in fig. ), we find that the maximal reduction in the x:a polymorphism ratio in ceu relative to yri is . % (see si section for details on the maximization). allowing the ratios to have different values before and after the split between yri and ceu but requiring them to be the same in both populations (model iii in fig. ), results in only a slightly greater maximal reduction of . % in the x:a polymorphism ratio. further allowing for population specific parameter values after the split (model iv in fig. ), we find that the maximal reduction in the ratio in ceu relative to yri rises to %, which is greater than the reduction observed. these results illustrate, quite surprisingly, that fairly recent changes to life history traits (relative to the average age of neutral polymorphism in either population) can dramatically affect x:a polymorphism ratios. in particular, they show that the reduction in polymorphism ratio in ceu relative to yri can be explained by assuming that life history parameters varied within plausible ranges over time and among populations. ⁄ are allowed to vary within the ranges detailed in the text, and are chosen to maximize the extant reduction in polymorphism ratios in ceu relative to yri under the following constraints: (ii) constant ratios over time and populations; (iii) ratios can differ before and after the populations split but are the same in both populations; (iv) ratios are the same before the populations split but different after. the estimated reduction in polymorphism ratio in ceu relative to yri is shown for comparison. polymorphism ratios in six populations. next, we examine whether variation in life history can explain the polymorphism ratios observed in all six populations jointly. for comparison, we first consider the model without sex-specific life history, which expectedly yields a poor fit (fig. b ). next, we allow for sex-specific life history parameters (within the ranges detailed above) and let them vary among the intervals defined by the approximate split times among populations (fig. a) . in particular, we seek the parameter values that minimize a weighted squared distance between predicted and estimated polymorphism ratios (see si section ). allowing sex-specific life history parameters to vary over time but not among populations substantially improved the fit, but fails to account for some features, e.g., the ratio in yri (fig. b) . further allowing sex-specific life history parameters to differ after populations split from one another, we are able to closely match the point estimates for all six populations (with mean distance < . sem averaged over the observed estimates; fig. b ). comparison of estimated normalized, polymorphism x:a ratios with those predicated under the historical changes in population size shown in a, and assuming: i) no life history effects (black); ii) sex-specific life history parameters that vary among the demarked intervals and were chosen to best fit the estimates (red); iii) the best fit further allowing sex-specific life history parameters to vary among populations after they split (blue). see text and si section for details. life history traits during human evolution. our results illustrate that historical changes in sex-specific life history traits and in population size can explain the x:a polymorphism ratios in extant human populations. our analysis relied on somewhat arbitrary decisions to fit few extant polymorphism ratios using many 'historical' life history parameters, i.e., about possible parameter ranges, the time intervals in which they could vary, and the distance between predictions and estimates that was minimized. alternative decisions would doubtless result in other sets of parameters that match the estimates of polymorphism ratios to a similar degree (accounting for uncertainty). the specific set of values we found (fig. s ) should therefore be treated as one of many possibilities; narrowing these sets down will require bringing to bear richer summaries of the data (see discussion). nonetheless, our results suggest a few conclusions. the first is that ancestral human populations were highly polygynous, as explaining the polymorphism ratios in yri would be difficult otherwise. second, they indicate that non-african populations likely experienced a substantial reduction in polygyny and/or increase in male-biased generation times around the ooa bottleneck, helping to explain the large reduction in polymorphism ratios in non-african populations. third, we find that, quite surprisingly, fairly recent changes in sex-specific life history have had a substantial impact on extant diversity levels, and in particular can account for the reduction in ratios between european and asian populations. life history traits, and generation times in particular, affect x:a polymorphism ratios in multiple ways, and these effects can be surprisingly strong. in particular, we have shown that in humans, higher generation times in males than in females substantially decreases the mutation rate and increases coalescence rates on the x relative to autosomes. they also substantially enhance the reduction in the x:a ratio due to bottlenecks (or alternatively increase the ratio due to population growth), both by accelerating the response time in generations and by increasing the number of generations per unit time on the x relative to autosomes. these generation times effects compound those of higher reproductive variance in males (i.e., polygyny) that were explored by previous studies ( , , , , , ) . higher male variances decrease coalescence rates on x relative to autosomes and dampen the effects of changes in population sizes on x:a diversity ratios. as we show, considered jointly, these effects can explain observed x:a polymorphism ratios across human populations. while our results have clear implications about the values of life history traits in recent human evolution, our ability to draw quantitative conclusions is limited by remaining gaps in our knowledge about demographic history. current demographic inferences assume that the autosomal generation time and mutation rate were constant, whereas both have doubtless changed over time. ignoring such changes introduces errors in estimates of effective population sizes and in their assignment to past dates (i.e., in years). accounting for these errors is unlikely to change our qualitative conclusions, but would likely affect the life history parameter estimates. the same is true of demographic complications that we did not consider, including historical migration/admixture among populations ( ) and ancient introgression ( , ) , and more speculative sex biases in these processes ( , , ) . our analysis further relies on pedigree-based estimates of mutation rates in contemporary humans in order to model mutational effects on x:a polymorphism ratios. we used these estimates to infer x:a genealogical ratios and to relate models of historical life history trait values with extant x:a polymorphism ratios. in so doing, we assumed that mutation rates on the x are well approximated by the averages over rates in males and females, i.e., that / =f % + b f & (because pedigree-based estimates rely on autosomal mutations). although this assumption is inexact, given the evidence for x specific modifiers of mutation rates, the observed effects are fairly subtle ( ) . in the future, larger pedigree studies in humans, with a sufficient number of mutations on the x, should allow direct estimation of mutation rates on the x. our approach also assumed that male mutation bias and its dependence on generation times observed today hold for the entire period over which extant neutral diversity in human arose, e.g., over the past ~ . my ( ) . the evidence regarding evolutionary change in male mutation bias is contradictory. lineage-specific, divergence-based estimates of in great apes are extremely variable, with estimates of . for humans, . for chimpanzees, . for gorillas and . for orangutans ( ) (some but probably not most of this variation could be due to changing sex-ratios of generation times ( ) ). in contrast, pedigree-based estimates of in extant species spanning a much greater phylogenetic range, i.e., mammals, appear to be stable (albeit with large confidence intervals), and are in fact consistent with the estimates in humans (( - ); felix wu and molly przeworski, personal communication). larger pedigree-based studies in other catarrhine species will likely resolve this apparent conflict and inform the plausibility of our assumption. more generally, we note that pedigree-based estimates of the autosomal mutation rate have triggered a wholesale revision of the chronology of human evolution obtained from genetic data ( ) . similarly, our results call for a revision of human x:a polymorphism ratios in light of pedigree based estimates of the male mutation bias. novel insights about mutation may also facilitate direct inferences about historical changes in life history traits. such inferences could rely on the fact that different kinds of mutations have distinct dependencies on male and female generation times ( ) but share the same genealogies. it may therefore be possible to infer male and female generation times from the ratios of different kinds of mutations of the same age on x and autosome linked genealogies. it might also be possible to extend methods like msmc to utilize data about different kinds of mutations on the x and autosomes jointly, in order to infer historical changes in both generation times and effective population sizes, and possibly even sex-dependent migration between populations. while we focused our analysis on humans, for which there are more data, there is every reason to think that life history substantially affected x:a polymorphism ratios in other species as well. notably, sex differences in life history traits and changes in population size, as well as extensive variation in these factors among populations and closely related species, are pervasive in many taxa (e.g., among vertebrates ( )). it almost necessarily follows that the life history and particularly the generation time effects that we describe would have affected their x:a polymorphism ratios. the effect of life-history and mode of inheritance on neutral genetic variability selection, recombination, and dna polymorphism in drosophila. non neutral-evolution: theories and molecular data contrasting patterns of x-linked and autosomal nucleotide variation in drosophila melanogaster and drosophila simulans testing models of selection and demography in drosophila simulans the different levels of genetic diversity in sex chromosomes and autosomes revisiting an old riddle: what determines genetic diversity levels within species? genomic signatures of sex-biased demography: progress and prospects sex-biased evolutionary 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in recent human evolution contrasting x-linked and autosomal diversity across human populations search for gravitational-wave bursts from soft gamma repeaters a human population bottleneck can account for the discordance between patterns of mitochondrial versus nuclear dna variation population bottlenecks and patterns of human polymorphism population size changes reshape genomic patterns of diversity means, variances, and ranges in reproductive success: comparative evidence life history effects on neutral diversity levels of autosomes and sex chromosomes the origins, patterns and implications of human spontaneous mutation rate of de novo mutations and the importance of father's age to disease risk strong male bias drives germline mutation in chimpanzees new observations on maternal age effect on germline de novo mutations parental influence on human germline de novo mutations in , trios from iceland overlooked roles of dna damage and maternal age in generating human germline mutations 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sequence of the neandertal genome a high-coverage genome sequence from an archaic denisovan individual the strength of selection against neanderthal introgression signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human x chromosome and autosomes paternal age in rhesus macaques is positively associated with germline mutation accumulation but not with measures of offspring sociability reproductive longevity predicts mutation rates in primates direct estimation of mutations in great apes reconciles phylogenetic dating direct estimation of de novo mutation rates in a chimpanzee parentoffspring trio by ultra-deep whole genome sequencing striking differences in patterns of germline mutation between mice and humans frequency of mosaicism points towards mutation-prone early cleavage cell divisions. biorxiv an analysis of the relationship between metabolism, developmental schedules, and longevity using phylogenetic independent contrasts. the journals of gerontology. series a, biological sciences and medical sciences acknowledgements. we thank i. agarwal, p. moorjani and m. przeworski for many helpful discussions and comments on the manuscript. we also thank the editor and three anonymous reviewers for many helpful comments on an earlier version of this manuscript. key: cord- - mhimfsf authors: gray, nicholas; calleja, dominic; wimbush, alexander; miralles-dolz, enrique; gray, ander; de angelis, marco; derrer-merk, elfriede; oparaji, bright uchenna; stepanov, vladimir; clearkin, louis; ferson, scott title: is “no test is better than a bad test”? impact of diagnostic uncertainty in mass testing on the spread of covid- date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: mhimfsf testing is viewed as a critical aspect of any strategy to tackle epidemics. much of the dialogue around testing has concentrated on how countries can scale up capacity, but the uncertainty in testing has not received nearly as much attention beyond asking if a test is accurate enough to be used. even for highly accurate tests, false positives and false negatives will accumulate as mass testing strategies are employed under pressure, and these misdiagnoses could have major implications on the ability of governments to suppress the virus. the present analysis uses a modified sir model to understand the implication and magnitude of misdiagnosis in the context of ending lockdown measures. the results indicate that increased testing capacity alone will not provide a solution to lockdown measures. the progression of the epidemic and peak infections is shown to depend heavily on test characteristics, test targeting, and prevalence of the infection. antibody based immunity passports are rejected as a solution to ending lockdown, as they can put the population at risk if poorly targeted. similarly, mass screening for active viral infection may only be beneficial if it can be sufficiently well targeted, otherwise reliance on this approach for protection of the population can again put them at risk. a well targeted active viral test combined with a slow release rate is a viable strategy for continuous suppression of the virus. during the early stages of the united kingdoms sars-cov- epidemic, the british government's covid- epidemic management strategy was been influenced by epidemiological modelling conducted by a number of research groups [ , ] . the analysis of the relative impact of different mitigation and suppression strategies concluded that the "only viable strategy at the current time" is to suppress the epidemic with all available measures, including the lockdown of the population with schools closed [ , ] . similar analysis in other countries lead to over half the world population being in some form of lockdown by april and over % of global schools closed [ , ] . these analyses have highlighted from the beginning that the eventual relaxation of lockdown measures would be problematic [ ] . without a considered cessation of the suppression strategies the risk of a second wave becomes significant, possibly of greater magnitude than the first as the sars-cov- virus is now endemic in the population [ , ] . although much attention was focused on the number of tests being conducted and the effect that testing could have in supressing the disease [ ] [ ] [ ] . not enough attention has been given to the issues of imperfect testing, beyond matt hancock, uk secretary of state for health and social care, stating in a press conference on nd april that "no test is better than a bad test" [ ] . in this paper we will explore the validity of this claim. the failure to detect the virus in infected patients can be a significant problem in highthroughput settings operating under severe pressure, with evidence suggesting that this is indeed the case [ ] [ ] [ ] [ ] [ ] . the public are rapidly becoming aware of the difference between the 'have you got it?' tests for detecting active cases, and the 'have you had it?' tests for the presence of antibodies, which imply some immunity to covid- . what may be less obvious is that these different tests need to maximise different test characteristics. to be useful in ending lockdown measures, active viral tests need to maximise the sensitivity. high sensitivity reduces the chance of missing people who have the virus who may go on to infect others. there is an additional risk that an infected person who has been incorrectly told they do not have the disease, when in fact they do, may behave in a more reckless manner than if their disease status were uncertain. the second testing approach, seeking to detect the presence of antibodies to identify those who have had the disease would be used in a different strategy. this strategy would involve detecting those who have successfully overcome the virus, and are likely to have some level of immunity (or at least reduced susceptibility to more serious illness if they are infected again), so are relatively safe to relax their personal lockdown measures. this strategy would require a high test specificity, aiming to minimise how often the test tells someone they have had the disease when they haven't [ ] . a false positive tells people they have immunity when they don't, which may be worse than if people are uncertain about their viral history. the successes of south korea, singapore, taiwan and hong kong in limiting the impact of the sars-cov- virus has been attributed to their ability to deploy widespread testing, with digital surveillance, and impose targeted quarantines in some cases [ ] . this testing has predominantly been based on the use of reverse transcription polymerase chain reaction (rt-pcr) testing. during the h n pandemic the rapid development of high sensitivity pcr assay were employed early with some success in that global pandemic [ ] . these tests, when well targeted, clearly provide a useful tool for managing and tracking pandemics. these tests form the basis of much of the research into the incidence, dynamics and comorbidities of sars-cov- , but few, if any, of these studies give consideration to the impact of false test results [ ] [ ] [ ] [ ] [ ] . increasing reliance on lower-sensitivity tests to address capacity concerns is likely to make available data on confirmed cases more difficult to accurately utilise [ ] . it may be the case that false test results contribute to some of the counter-intuitive disease dynamics observed [ ] . there is evidence that both active infection [ ] [ ] [ ] [ ] [ ] and antibody [ ] [ ] [ ] tests lack perfect sensitivity and specificity even in best-case scenarios. alternative screening methods such as chest x-rays may be found to have high sensitivity based on biased data [ ] or may simply perform poorly even compared to imperfect rt-pcr tests [ ] . the foundation for innovative in order to answer this question there are a number of important statistics: • sensitivity σ-out of those who actually have the disease, that fraction that received a positive test result. • specificity τ-out of these who did not have the disease, the fraction that received a negative test result. the statistics that characterise the performance of the test are computed from a confusion matrix (table ) . we test n infected people who have covid- , and n healthy people who do not have covid- . in the first group, a people correctly test positive and c falsely test negative. among healthy people, b will falsely test positive, and d will correctly test negative. from this confusion matrix the sensitivity is given by ( ) and the specificity by ( ). s ¼ a n infected ð Þ sensitivity is the ratio of correct positive tests to the total number of infected people involved in the study characterising the test. the specificity is the ratio of the correct negative tests to the total number of healthy people. importantly, these statistics depend only on the test itself and do not depend on the population the test is intended to be used upon. when the test is used for diagnostic purposes, the characteristics of the population being tested become important for interpreting the test results. to interpret the diagnostic value of a positive or negative test result the following statistics must be used: • prevalence p-the proportion of people in the target population that have the disease tested for. • positive predictive value ppv-how likely one is to have the disease given a positive test result. • negative predictive value npv-how likely one is to not have the disease, given a negative test result. the ppv and npv depend on the prevalence, and hence depend on the population you are focused on. this may an entire nation or region, a sub-population with covid- compatible symptoms, or any other population you may wish to target. the ppv and npv can be calculated using bayes' rule: to illustrate the impact of prevalence on ppv, for a test with σ = τ = . , if prevalence p = . , then the ppv = . . therefore, a positive result only indicates a % chance that an individual will have the disease given that they have tested positive, even though the test is highly accurate. fig shows why, for test subjects there will be similar numbers of true and false positives even with high sensitivity and specificity of %. in contrast, using the same tests on a sample with a higher prevalence p = . we find the ppv = . , see fig . similarly, the npv is lower when the prevalence is higher. sir models offer one approach to explore infection dynamics, and the prevalence of a communicable disease. in the generic sir model, there are s people susceptible to the illness, i people is "no test is better than a bad test"? infected, and r people who are recovered with immunity. the infected people are able to infect susceptible people at rate β and they recover from the disease at rate γ [ ] , fig shows how people move between the different states of an sir model. once infected persons have recovered from the disease they are unable to become infected again or infect others. this may be because they now have immunity to the disease or because they have unfortunately died. to explore the effect of imperfect testing on the disease dynamics when strategies testing regimes are employed to relax lockdown measures, three new classes were added to the model. the first is a quarantined susceptible state, q s , the second is a quarantined infected state, q i , and the third is people who have recovered but are in quarantine, q r , as shown in is "no test is better than a bad test"? the present model is similar to other sir models that take into account the effect of quarantining regimes on disease dynamics, such as lipsitch et al. ( ) [ ] or giordano et al. ( ) [ ] . lipsitch et al. implement quarantine in their model but do not incorporate the effects on the dynamics from imperfect testing, nor do they consider how the quality and scale of an available test affect the spread of a disease. diagnostic uncertainty plays no part in the model they present. likewise, giordano et al reduce population based diagnostic strategies to two parameters which confound test capacity, test targeting, and diagnostic uncertainty. again, they do not investigate the role that diagnostic uncertainty plays in the spread of a disease. the intent of this model is not to create a more sophisticated sir model, but to investigate how diagnostic uncertainty affects the dynamics of an epidemic. the model evaluates each day's population-level state transitions. there are two possible tests that can be performed: • an active virus infection test that is able to determine whether or not someone is currently infectious. this test is performed on some proportion of the un-quarantined population (s + i + r). it has a sensitivity of σ a and a specificity of τ a . • an antibody test that determines whether or not someone has had the infection in the past. this is used on the fraction of the population that is currently in quarantine but not infected (q s + q r ) to test whether they have had the disease or not. this test has a sensitivity of σ b and a specificity of τ b . each test is defined by a number of parameters. testing each day is limited by the test capacity c, the maximum number of tests that can be performed each day. each day a population n will be submitted for testing. the targeting capability of the test, t indicates the probability that an individual submitted for testing is positive, this is effectively the ppv of the initial screening effort. this results in a number of individuals m being considered for screening who are negative, of which k will be tested. targeting must be imperfect, as if it were perfect there would be no need for testing. unless otherwise stated, scenarios consider a default targeting of t = . , representing an extremely effective screening capability that is nonetheless imperfect. if daily testing targets are a goal regardless of the prevalence of the illness, t can be overruled to ensure n � c for example. this condition is referred to as strict capacity and is denoted with boolean parameter g, defaulting to true for all scenarios. tests can also be conducted periodically by changing the test interval parameter d. these default to , i.e. daily testing. each test has unique parameters, so for example test a (active virus infection test) has a targeting parameter t a whilst test b (antibody test) has t b . the parameters σ, τ, t, c, g and d define a test. a person in any category who tests positive in an active virus test transitions into the corresponding quarantine state, where they are unable to infect anyone else. a person, in q s or q r , who tests positive in an antibody test transitions to s and r respectively. any person within i or q i who recovers transitions to r, on the assumption that the end of the illness is clear and they will know when they have recovered. for this parameterisation the impact of being in the susceptible quarantined state, q s , makes an individual insusceptible to being infected. similarly, being in the infected quarantined state, q i , individuals are unable to infect anyone else. in practicality there is always leaking, no quarantine is entirely effective, but for the sake of exploring the impact of testing uncertainty these effects are neglected from the model. other situations may require including this effect. the sir model used in this paper uses discrete-time binomial sampling for calculating movements of individuals between states. for a defined testing strategy these rates are defined as follows: in eq , bin(n, p) refers to a binomial distribution with count n and rate p, h(n, k, m) refers to a hypergeometric distribution with populations n and k and a sample size m. the model must be initialised with a defined population split between the six states. at each time step t, the model calculates the number of persons moving between each state in the order defined above. the use of binomial and hypergeometric sampling was prompted by a desire to incorporate aleatory uncertainty in each movement. the current approach does not account for epistemic uncertainty, fixing the model parameters σ, τ, c, t and d. a discrete time model was selected to allow for comparisons against available published data detailing recorded cases and recoveries on a day-by-day basis. if the tests were almost perfect, then we can imagine how the epidemic would die out very quickly by either widespread infection or antibody testing with a coherent management strategy. a positive test on the former and the person is removed from the population, and positive test on the latter and the person, unlikely to contract the disease again, can join the population. more interesting are the effects of incorrect test results on the disease dynamics. if someone falsely tests positive in the antibody test, they enter the susceptible state. similarly, if an infected person receives a false negative for the disease they remain active in the infected state and hence can continue the disease propagation and infect further people. in order to explore the possible impact of testing strategies on the relaxation of lockdown measures several scenarios have been analysed. these scenarios are illustrative of the type of impact, and the likely efficacy of a range of different testing configurations. • immediate end to lockdown scenario: this baseline scenario is characterised by a sudden relaxation of lockdown measures. • immunity passports scenario: a policy that has been discussed in the media [ ] [ ] [ ] . analogous to the international certificate of vaccination and prophylaxis, antibody based testing would be used to identify those who have some level of natural immunity. • incremental relaxation scenario: a phased relaxation of lockdown is the most likely policy that will be employed. to understand the implications of such an approach this scenario has explored the effect of testing capacity and test performance on the possible disease dynamics under this type of policy. under the model parameterisation this analysis has applied an incremental transition rate from the q s state to the s state, and q r to r. whilst the authors are sensitive to the sociological and ethical concerns of any of these approaches, the analysis presented is purely on the question of efficacy. for the purpose of the analysis we have selected a population similar in size to the united kingdom, . × people, β and γ were set to . and . respectively, this was ensure that r value of the model was broadly in line with other models [ , ] . under the baseline scenario, characterised by the sudden and complete cessation of lockdown measures, we explored the impact of infection testing. under this formulation the initial conditions of the model in this scenario is that the all of the population in q s transition to s in the first iteration. the impact of infection testing under this scenario was analysed in fig using the parameters shown in table . these scenarios consider the impact of attempts to control the disease through increased testing capacity and a more sensitive test. a test capacity range between × and × was considered as representative of the capabilities of a country such as the uk. to illustrate the sensitivity of the model to testing scenarios an evaluation was conducted with a range of infection test sensitivities, from % (i.e of no diagnostic value) to %. the specificity of these tests has a negligible impact on the disease dynamics in these scenarios. a false positive would mean people are unnecessarily removed from the susceptible population, but the benefit of a reduction in susceptible population is negligibly small. as would be expected the model indicates a second wave is an inevitability and as many as million people could become infected within days. a high-sensitivity test has little impact table . https://doi.org/ . /journal.pone. .g is "no test is better than a bad test"? beyond quarantining a slightly higher percentage of the population if capacities are low. at higher capacities this patterns remains, though peak infection counts are marginally reduced. overall it is clear that reliance on infection testing, even with a highly sensitive test and high capacities, is not enough to prevent widespread infection. the immunity passport is an idiom describing an approach to the relaxation of lockdown measures that focuses heavily on antibody testing. wide-scale screening for antibodies in the general population promises significant scientific value, and targeted antibody testing is likely to have value for reducing risks to nhs and care-sector staff, and other key workers who will need to have close contact with covid- sufferers. the authors appreciate these other motivations for the development and roll-out of accurate antibody tests. this analysis however focuses on the appropriateness of this approach to relaxing lockdown measures by mass testing the general population. antibody testing has been described as a 'game-changer' [ ] . some commentators believe this could have a significant impact on the relaxation of lockdown measures [ ] , but others note that there are severe ethical, logistical and medical concerns which need to be resolved before antibody testing could support a strategy such as this [ ] . much of the discussion around antibody testing in the media has focused on the performance and number of these tests. the efficacy of this strategy however is far more dependent on the prevalence of antibodies (seroprevalence) in the general population. without widescale antibody screening it is impossible to know the seroprevalence in the general population, so there is scientific value in such an endeavour. however, the seroprevalence is the dominant factor to determine how efficacious antibody screening would be for relaxing lockdown measures. presumably, only people who test positive for antibodies would be allowed to leave quarantine. the more people in the population with antibodies, the more people will get a true positive, so more people would be correctly allowed to leave quarantine (under the paradigms of an immunity passport). the danger of such an approach are false positives. we demonstrate the impact of people reentering the susceptible population who have no immunity. we assume their propensity to contract the infection is the same as those without the false sense of security a positive test may engender. on an individual basis, and even at the population level, behavioural differences between those with false security from a positive antibody test, versus those who are uncertain about their viral history could be significant. the model parametrisation here does not include this additional confounding effect. to simulate the seroprevalence in the general population the model is preconditioned with different proportions of the population in the q s and q r states. this is analogous to the proportion of people that are currently in quarantine who have either had the virus and developed some immunity, and the proportion of the population who have not contracted the virus and is "no test is better than a bad test"? have no immunity. of course the individuals in these groups do not really know their viral history, and hence would not know which state they begin in. the model evaluations explore a range of sensitivity and specificities for the antibody testing. these sensitivity and specificities, along with the capacity for testing, govern the transition of individuals from q r to r (true positive tests), and from q s to s (false positive tests). each of the plots in figs and show the effect of different seroprevalence in the population. to be clear, this is the proportion of the population that has contracted the virus and recovered but are in quarantine. the analysis has explored a range of seroprevalence from . % to %. fig explores the impact of a variation in sensitivity, from a test with % sensitivity to tests with a high sensitivity of %. it can be seen, considering the top row of fig , that the sensitivity of the test has no discernible impact on the number of infections. the seroprevalence entirely dominates. this is possibly counter intuitive, but as was discussed above, even a highly accurate test produces a very large number of false positives when seroprevalence is low. in this case that would mean a large number of people are allowed to re-enter the population, placing them at risk, with a false sense of security that they have immunity. the bottom row of fig shows the proportion of the entire population leaving quarantine over a year of employing this policy. at low seroprevalence there is no benefit to better table . performing tests. this again may seem obscure to many readers. if you consider the highest seroprevalence simulation, where % of the population have immunity, higher sensitivity tests are of course effective at identifying those who are immune, and gets them back into the community much faster. a more concerning story can be seen when considering the graphs in fig . now we consider a range of antibody test specificities. going from % to %. low specificities (τ < . ) table . https://doi.org/ . /journal.pone. .g lead to extreme second peaks, and could possibly lead to more. this is due to the progressive release of false-positives from the quarantined population, which eventually swells the susceptible population to a size where the infection count can resume exponential growth. high specificities avoid this at the cost of a prolonged lockdown, which is naturally limited by the lower false-positive rate. clearly some means of release beyond immunity passports would be required to avoid this scenario. notably, a reasonably specific test (τ b = . ) is capable of restraining a second peak to reasonably low levels regardless of seroprevalence. this may allow for other means of reducing lockdown measures, though with very low seroprevalence this could still be a potentially risky strategy. the dangers of neglecting uncertainties in medical diagnostic testing are pertinent to this decision [ ] . considering the above, some form of incremental relaxation of lockdown seems appropriate. this could take many forms, it could be an incremental restoration of certain activities such as school openings, permission for the reopening of some businesses, the relaxation of stay-athome messaging, etc. under the parameterisation chosen for this analysis the model is not sensitive to any particular policy change. we consider a variety of rates of phased relaxations to quarantine. to model these rates we consider a weekly incremental transition rate from q s to s, and q r to r. in fig , three weekly transition rates have been applied: %, % and % of the quarantined population. whilst in practice the rate is unlikely to be uniform as decision makers would have the ability to update their timetable as the impact of relaxations becomes apparent, it is useful to illustrate the interaction of testing capacity and release rate. the model simulates these rates of transition for a year, with a sensitivity and specificity of % for active virus tests. the specifics of all the runs are detailed in table . fig shows five analyses, with increasing capacity for the active virus tests. in each, the incremental transition rates are applied with a range of targeting capabilities. the value of . used previously represents an unrealistically extreme case of effective targeting. the ppv, as discussed above, has a greater dependence on the prevalence (at lower values) in the tested population than it does on the sensitivity of the tests, the same is true of the specificity and the npv. it is important to notice that higher test capacities cause a higher peak of infections for higher release rates. this has a counterintuitive explanation. when there is the sharpest rise in the susceptible population (i.e., high rate of transition), the virus rapidly infects a large number of people. when these people recover after around two weeks they become immune and thus cannot continue the spread of the virus. however, when the infection testing is conducted with a higher capacity up to , units per day, these tests transition some active viral carriers into quarantine, so the peak is slightly delayed providing more opportunity for those released from quarantine later to be infected, leading to higher peak infections. this continues until the model reaches effective herd immunity after which the number of infected in the population decays very quickly. having higher testing capacities delays but actually has the potential to worsen the peak number of infections. at % release rate, up to a capacity of testing of , these outcomes are insensitive to the prevalence of the disease in the tested population. this analysis indicates that the relatively fast cessation of lockdown measures and stay-home advice would lead to a large resurgence of the virus. testing capacity of the magnitude stated as the goal of the uk government would not be sufficient to flatten the curve in this scenario. the % release rate scenario indicates that a slow release by itself is sufficient to lower peak infections, but potentially extends the duration of elevated infections. the first graph of the top row in fig shows that the slow release rate causes a plateau at a significantly lower number of infections compared to the other release rates. poorly targeted tests at capacities less than , show similar consistent levels of infections. however, with a targeted test having a prevalence of % or more, the % release rate indicates that even with , tests per day continuous suppression of the infection may be possible. the per-day testing capacity is varied across the five columns of graphs. rate, the percentage of the initial quarantined population being released each week is varied among rows. the prevalence of infections in the tested population is varied among different colours. to facilitate comparison within each column of graphs, the gray curves show the results observed for other rates and prevalences with the same testing intensity. model parameters are shown in table . https://doi.org/ . /journal.pone. .g at the rate of % of the population in lock-down released incrementally each week the infection peak is suppressed compared to the % rate. the number of infections would remain around this level for a significantly longer period of time, up to months. there is negligible impact of testing below a capacity of , tests. however, with a test capacity of , tests the duration of the elevated levels of infections could be reduced if the test is extremely well targeted (t a = . ), reducing the length of necessary wide-scale lockdown. if this level of targeting is not achieved, increasing capacity may again increase peak infections, so care must be taken to ensure a highly targeted testing strategy. this analysis does support the assertion that a bad test is potentially worse than no tests, but a good test is only effective in a carefully designed strategy. more is not necessarily better and over estimation of the test accuracy could be extremely detrimental. this analysis is not a prediction; the numbers used in this analysis are estimates and the sirq model used is unlikely to be detailed enough to inform policy decisions. as such, the authors are not drawing firm conclusions about the absolute necessary capacity of tests. nor do they wish to make specific statements about the necessary sensitivity or specificity of tests or the recommended rate of release from quarantine. the authors do, however, propose some conclusions that would broadly apply when testing and quarantining regimes are used to suppress epidemics, and therefore believe they should be considered by policy makers when designing strategies to tackle covid- . • diagnostic uncertainty can have a large effect on the dynamics of an epidemic. and, sensitivity, specificity, and the capacity for testing alone are not sufficient to design effective testing procedures. policy makers need to be aware of the accuracy of the tests, the prevelence of the disease at increased granularity and the characteristics of the target population, when deciding on testing strategies. • caution should be exercised in the use of antibody testing. assuming that the prevalence of antibodies is low, it is unlikely antibody testing at any scale will support the end of lockdown measures. and, un-targeted antibody screening at the population level could cause more harm than good. • antibody testing, with a high specificity may be useful on an individual basis, it has scientific value, and could reduce risk for key workers. but any belief that these tests would be useful to relax lockdown measures for the majority of the population is misguided. • the incremental relaxation to lockdown measures, with all else equal, would significantly dampen the increase in peak infections, by order of magnitude with a faster relaxation, and orders of magnitude with a slower relaxation. • as the prevelence of the disease is suppressed in different regions, it may be the case that small spikes in cases could be the result of false positives. this problem is potentially exacerbated by increased testing in localities in response to small increases in positive tests. policy decisions that depend on small changes in the number of positive tests may, therefore, be flawed. • for infection screening to be used to relax quarantine measures the capacity needs to be sufficiently large but also well targeted to be effective. for example this could be achieved through effective contact tracing. untargeted mass screening at any capacity would be ineffectual and may prolong the necessary implementation of lockdown measures. epidemiological models used for policy making in real time will need to take into account the impact of diagnostic uncertainty of testing, as well as the dynamical behaviour and sensitivity analyses of modelled parameters in an appropriately complex model that may need to include quarantining, contact tracing and other surveillance strategies, test availability and targeting, and multiple subpopulations of susceptible, infected and recovered categories. covid- : government announces moving out of contain phase and into delay phase scaling up our testing programmes. department of health and socal care impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand. imperial college covid- response team pm address to the nation on coronavirus half of humanity now on lockdown as countries call for confinement covid- impact on eduction the effect of control strategies to reduce social mixing on outcomes of the covid- epidemic in wuhan, china: a modelling study. the lancet public health first-wave covid- transmissibility and severity in china outside hubei after control measures, and second-wave scenario planning: a modelling impact assessment. the lancet who director-general's opening remarks at the media briefing on covid- - offline: covid- and the nhs -"a national scandal offline: covid- -bewilderment and candour. the lancet coronavirus press conference coronavirus and the race to distribute reliable diagnostics why the coronavirus test gives so many false negatives difficulties in false negative diagnosis of coronavirus disease : a case report if you have coronavirus symptoms, assume you have the illness, even if you test negative are coronavirus tests accurate? report : role of testing in covid- control detecting pandemic influenza a (h n ) virus infection: availability of diagnostic testing led to rapid pandemic response epidemiology and transmission of covid- in shenzhen china: analysis of cases and , of their close contacts. medrxiv early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia spread of sars-cov- in the icelandic population modelling the covid- epidemic and implementation of population-wide interventions in italy projecting the transmission dynamics of sars-cov- through the postpandemic period updates on covid- in republic of korea development and clinical application of a rapid igm-igg combined antibody test for sars-cov- infection diagnosis evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of -ncov infections abstract interim guidelines for collecting, handling, and testing clinical specimens from persons for coronavirus disease (covid- ) correlation of chest ct and rt-pcr testing in coronavirus disease evaluation of novel antigen-based rapid detection test for the diagnosis of sars-cov- in respiratory samples. available at ssrn potential false-negative nucleic acid testing results for severe acute respiratory syndrome coronavirus from thermal inactivation of samples with low viral loads performance of vivadiag covid- igm/igg rapid test is inadequate for diagnosis of covid- in acute patients referring to emergency room department rapid point-of-care testing for sars-cov- in a community screening setting shows low sensitivity prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal sars-cov- diagnostics: performance data point-of-care versus lab-based testing: striking a balance molecular and antibody point-of-care tests to support the screening, diagnosis and monitoring of covid- . oxford covid- evidence service transmission dynamics and control of severe acute respiratory syndrome why it's too early to start giving out immunity passports' could speed up return to work after covid- britain has millions of coronavirus antibody tests, but they don't work the reproductive number of covid- is higher compared to sars coronavirus euro surveillance: bulletin europeen sur les maladies transmissibles = european communicable disease bulletin boris johnson and donald trump talk up potential'game-changer' scientific advances on coronavirus developing a national strategy for serology (antibody testing) in the united states calculated risks: how to know when numbers deceive you key: cord- - ttt fgr authors: cardoso, ben-hur francisco; gonccalves, sebasti'an title: urban scaling of covid- epidemics date: - - journal: nan doi: nan sha: doc_id: cord_uid: ttt fgr susceptible-invective-recovered (sir) mathematical models are in high demand due to the covid- pandemic. they are used in their standard formulation, or through the many variants, trying to fit and hopefully predict the number of new cases for the next days or weeks, in any place, city, or country. such is key knowledge for the authorities to prepare for the health systems demand or to apply restrictions to slow down the infectives curve. even when the model can be easily solved ---by the use of specialized software or by programming the numerical solution of the differential equations that represent the model---, the prediction is a non-easy task, because the behavioral change of people is reflected in a continuous change of the parameters. a relevant question is what we can use of one city to another; if what happened in madrid could have been applied to new york and then, if what we have learned from this city would be of use for s~ao paulo. with this idea in mind, we present an analysis of a spreading-rate related measure of covid- as a function of population density and population size for all us counties, as long as for brazilian cities and german cities. contrary to what is the common hypothesis in epidemics modeling, we observe a higher {em per-capita} contact rate for higher city's population density and population size. also, we find that the population size has a more explanatory effect than the population density. a contact rate scaling theory is proposed to explain the results. the epidemic of covid- that started in the chinese city of wuhan in december of , was declared a pandemic on march th, by the world health organization (who). presently, the epicenter is in the us, while cases still are growing in many european countries. soon, it will shift its center of gravity to russia or brazil, where the epidemic has the potential to hit even worse than in the us. many groups still struggle to get precise median and long term predictions of the number of expected cases, especially hospitalized or icu ones. such is because the epidemic parameters are continuously changing as the population changes its behavior, with or without government interventions [ ] . however, some general properties can already be identified across aggregated data, specifically related to demographic characteristics. to give ground to our proposed analysis, which is to compare empirical municipal-level data in some countries, we use a version of the sir model, which we call the sird model, because of the fourth d compartment. in this simple model, each municipal-level region (city or county) with population size n and land area a is composed of the following epidemiological compartments: susceptible (s), infected (i), recovered (r), and dead (d). considering only within-county transmission, the dynamics of these compartments is driven by the following system of differential equations [ where β is the transmission rate, γ is the removal rate, and φ is the case fatality rate. the n factor in the denominator makes β a disease only parameter, supposedly independent of the size or other characteristic of the population. indeed, in the book of keeling and rohani [ ] this formulation is referred to as frequency-dependent (or mass action) transmission. called it proportionate mixing by anderson and may [ ] , it assumes that the number of contacts is independent of the population size, resulting in similar patterns of transmission, whether it is a town or a large city. however, in the unprecedented evidence that we are collecting from the ongoing covid- pandemic, that common intuition seems not to be generally valid. on the opposite side, there is the pseudo-mass action formulation [ ] , in which the infection rate is directly proportional to the population size -which is not usually applied to human infectious diseases. our analysis shows that none of these extreme formulations can satisfactorily explain the available covid- data. the best fit corresponds to a formulation that is somehow in between those ones, and which can be explained in terms of a contact rate scaling theory. the time evolution of these compartments is governed by the three parameters, φ, γ, and β. the last one can be factorized as β = pc, where p is the probability of transmission and c is the per capita contact rate [ ] . the probability of infection p is a characteristic of the disease, most likely universal, and a key to epidemics because if it is too low, we would probably not have an outbreak. c, on the other side, condenses all the human factors that give rise to different epidemic patterns in different places, countries, or cultures. it is the only parameter that non-pharmaceutical interventions, like activity restrictions or lock-downs, can modify. yet, we will restrict ourselves here to its urban dependency. there are two main competing hypothesis that try to explain how c varies with n and a: the population size driven contact rate, where c = c(n ); and the population density driven contact rate, stating that c = c(ρ), where ρ = n/a. while the first approach assumes that the social mobility network grows in larger areas, allowing more distant people to interact [ ] , the second one assumes that the length traveled by the individuals is invariant of the city's size [ ] . intriguingly, based on data of disease transmission in the united states, both approaches appear to be valid [ , , ] . the reason for this is the quasi-linear correlation between density and size population of the us's counties, as shown in fig. . indeed, we have found that the best fit is ρ ∝ n λ , with λ ≈ . . assuming a linear relation instead, ρ = kn gives an equally valid fit, where k = a − = . km − . an almost constant density across counties, or no correlation between ρ and n cannot explain the data. note that from the value of the constant k we can obtain a typical county diameter in the united states of . km. in addition to the us, we study the covid- transmission in brazil's and germany's cities. in these two countries, the city's population size does not correlate well with their population density (see fig. ). the linear fitting, ρ = kn , is weak for the brazilian cities and almost nonexistent for germany. the constant case also cannot explain the data. since there is no correlation between ρ and n , we can use these two countries to check the validity of the population size-driven or the population density-driven approaches. the results can be useful during the present covid- pandemic and for futures ones. let assume individuals distributed uniformly in a two-dimensional space according to a density ρ. as introduced by noulas et al [ ] , we can expect that the individual j interacts with the individual i with probability it can be drastically attenuated or even suppressed by the use of masks, for example. where rank i (j) is the number of neighbors closer to i than j and ≤ α ≤ is a scaling factor. assuming that the distance between these two individuals is r, we have that first, since ≤ p ≤ , we must impose a bottom cutoff radius r such that secondly, it is natural to assume an upper cutoff radius r for long distances such that p (r > r ) = . so, the per capita contact rate is given by where a ≡ πr is the coverage area of individual mobility and the / factor eliminate the double counting. this result generalizes the α = case deduced by krumme et al [ ] , where on the other hand, the population density driven approach states that a is invariant, thus from the same eq. we got we use the municipal-level time series of confirmed cases and deaths for united sates [ ] , brazil [ ] and germany [ ] . also, we use the municipal-level population size and land area for united sates [ , ] , brazil [ , ] and germany [?]. due to social distancing measures, it is expected that the value of β varies in time, but we can consider it as a constant for a sufficient short interval. so, let be [t, t + ∆t] such that s(t + ∆t) < s(t) and d(t + ∆t) > d(t). assuming that β(t) is constant in this interval, we get form eq. : where b is the integration constant. aiming to cancel some day of week seasonality bias, we choice ∆t = week. now, noting the s is the population size minus the confirmed cases, we can construct a weekly time-series of d (see fig. for an example) such that . we can note the maximum value in the th week, at the beginning of the pause order [ ] . assuming that the social distancing measures are sufficiently distributed among cities and time, we can expect that d varies in time around a value proportional to the theoretical one. with the population density-driven contact rate hypothesis, we relate the population density of each city with its d /a value, where d is the time average of d (t) for this location. so, in this framework, we have considering the population size-driven contact rate hypothesis, we plot the population size of each city and its d , where d is the time average of d (t) for this location. in this approach, we expect results if the mass action (constant contact rate) is valid, we expect that d /a scales linearly with ρ. in the another extreme, if the pseudo-mass action (c ∝ n ) is valid, we expect that d /a is a constant. in figs. , and we show, respectively, the comparison between d /a and the population density for different counties of united states, cities of brazil, and cities of germany. we can note that the model (in eq ) provides a good fit for united states, better than the mass action hypothesis. however, this not happens in brazil and germany, where the model (in eq ) have almost the same predictability that this hypothesis. the pseudo-mass-action cannot explain these results. this is also true in a more general scope, as shown in fig. . this result can indicate that the contact rate is, in fact, related with population size and not with the population density. the case of united states can be explained by the linear scaling between their county's population size and population density, as show before in fig. . if the mass action (constant contact rate) is valid, we expect that d scales linearly with n . in the another extreme, if the pseudo-mass action (c ∝ n ) is valid, we expect that d is a constant. in figs. , and we show, respectively, the comparison between d and the population size for different counties of united states, cities of brazil, and cities of germany. now, we can note that the model (in eq ) provides a good fit for the three countries and are better than the mass action hypothesis. the pseudo-mass action cannot explain these results. this can be viewed in a more general scope in fig. , where we found universally that α ≈ / . our main hypothesis is that closer people interact more frequently. so, we expect that if we increase the geographical scale (counties → metropolitan areas → states), we reduce the dependence between contact rate and the population size. in fig. and , we respectively show the relation between d and n for metropolitan areas and states of united states. as expected, the scaling dependence is higher for geographical scales with more granularity. the scaling α ≈ . for metropolitan areas is very close to the power-law scaling found in a previous work [ ] . to do so, using the approximation s ≈ n for short-times, they measure the growth rate of confirmed cases of covid- by an exponential fit between march th and march th. here we follow the approach described in the methodology section, since it not involves approximations, uses all available data (both confirmed cases and deaths) and allows the weekly variation of β, since now we have access of a longer period. the epidemic dynamics are traditionally explained by two hypothesis: the mass action and the pseudo-mass action. here we shown empirically that neither is good to describe the data. also, we develop a theory to explain the found relation. our analysis and results give support to the validity of the population size driven contact rate for the covid- pandemic. this result can also explain the super-linear scaling of criminality in brazil [ ] , japan [ ] and united states [ ] . such is the the downside of leaving in large urban centers. from our analysis, it is clear that the scaling is valid at the municipal, county, or city level. if we make it broader at regions, province or state level, it is washed out by the different scales averaged over such large regions. this conclusion can provide useful insight regarding the urgent problem that cities, and the world in general, are facing. as others authors [ ] already pointed out, larger cities require more strict social distancing policies. on the other side, smaller cities may relax controls before larger cities. trend analysis of the covid- pandemic in china and the rest of the world modeling infectious diseases in humans and animals infectious diseases of humans the scaling of contact rates with population density for the infectious disease models the origins of scaling in cities urban characteristics attributable to density-driven tie formation dynamics of measles epidemics: estimating scaling of transmission rates using a time series sir model a tale of many cities: universal patterns in human urban mobility cssegi sand data / covid- brasil io / covid- county population totals census urban and rural classification and urban area criteria declaring a disaster emergency in the state of new york covid- attack rate increases with city size. mansueto institute for urban innovation research paper forthcoming the statistics of urban scaling and their connection to zipf's law the scaling of crime concentration in cities key: cord- - f xph y authors: halczok, tanja k.; fischer, kerstin; gierke, robert; zeus, veronika; meier, frauke; treß, christoph; balkema-buschmann, anne; puechmaille, sébastien j.; kerth, gerald title: evidence for genetic variation in natterer’s bats (myotis nattereri) across three regions in germany but no evidence for co-variation with their associated astroviruses date: - - journal: bmc evol biol doi: . /s - - - sha: doc_id: cord_uid: f xph y background: as bats have recently been described to harbor many different viruses, several studies have investigated the genetic co-variation between viruses and different bat species. however, little is known about the genetic co-variation of viruses and different populations of the same bat species, although such information is needed for an understanding of virus transmission dynamics within a given host species. we hypothesized that if virus transmission between host populations depends on events linked to gene flow in the bats, genetic co-variation should exist between host populations and astroviruses. results: we used nuclear and one mitochondrial microsatellite loci to analyze the genetic population structure of the natterer’s bat (myotis nattereri) within and among populations at different geographical scales in germany. further, we correlated the observed bat population structure to that of partial astrovirus sequences ( – nt fragments of the rna-dependent rna polymerase gene) obtained from the same bat populations. our analyses revealed that the studied bat colonies can be grouped into three distinct genetic clusters, corresponding to the three geographic regions sampled. furthermore, we observed an overall isolation-by-distance pattern, while no significant pattern was observed within a geographic region. moreover, we found no correlation between the genetic distances among the bat populations and the astrovirus sequences they harbored. even though high genetic similarity of some of the astrovirus haplotypes found in several different regions was detected, identical astrovirus haplotypes were not shared between different sampled regions. conclusions: the genetic population structure of the bat host suggests that mating sites where several local breeding colonies meet act as stepping-stones for gene flow. identical astrovirus haplotypes were not shared between different sampled regions suggesting that astroviruses are mostly transmitted among host colonies at the local scale. nevertheless, high genetic similarity of some of the astrovirus haplotypes found in several different regions implies that occasional transmission across regions with subsequent mutations of the virus haplotypes does occur. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. with their particular social, ecological, physiological and immunological traits, bats provide unique hosts for many viruses to co-evolve with (e.g. [ , ] ). indeed, bats are increasingly recognized as reservoirs for a wide range of viruses, some of which carry a zoonotic potential, for example rabies and other viruses of the genus lyssavirus, sars-like, mers-like and other coronaviruses [ ] [ ] [ ] [ ] . consequently, several studies have investigated the genetic co-variation between different bat species and their associated viruses [ , ] . however, much less is known about genetic co-variation of viruses and different populations of the same bat species, although such information is required to gain a better understanding of the transmission dynamics within a given host species (e.g. [ , ] ). the natterer's bat (myotis nattereri kuhl sensu lato [ ] ) is a non-migratory vespertilionid bat that is widespread throughout europe with the exception of the iberian and italian peninsula and the south of france [ ] . while this species uses underground sites for hibernation during the winter months, it mostly roosts in trees and buildings during summer forming maternity colonies that consist of female bats and their juveniles as well as occasionally some males [ , ] . males typically roost either individually or in small groups in the vicinity of the maternity colonies [ ] . male and female natterer's bats have been found to exhibit philopatry even though males leave their natal colony but stay in its vicinity [ ] . mating takes place during autumn at swarming sites that are typically up to km away from the summer colony [ ] . recently, various viruses have been reported to be harbored by m. nattereri [ ] , including herpes- [ ] , lyssa- [ ] and astroviruses (e.g. [ ] ). the astroviridae form a large family of non-enveloped, positive-sense, singlestranded rna viruses [ ] . astroviruses are mostly transmitted via the fecal-oral route [ ] and may cause diarrhea in many animal species, including humans [ ] . however, the route of transmission in bats has not yet been elucidated. even though astroviruses have been detected in a variety of species [ ] , bats have been hypothesized to be a potential reservoir host in europe and asia [ , ] . the high prevalence and diversity of astroviruses harbored by bats is remarkable [ , , ] and their capability to cross species barriers and become adapted to new hosts, including spill-over to other taxa, has been suggested [ ] . due to the occurrence of astroviruses in animals in close contact to humans, e.g. livestock and also bats using human habitation as roosting, it has been argued that astroviruses should be considered as potential candidates for zoonotic infections (e.g. [ ] ). however, almost nothing is known about the transmission of astrovirus among different populations of their bat hosts. we studied patterns of population genetic structure and dispersal of myotis nattereri within and among three geographic regions of germany using both nuclear and mitochondrial microsatellite markers. the population genetic structure of m. nattereri has previously only been investigated in the united kingdom (uk; [ ] ). however, the population genetic structure of bats occurring in the uk may be affected by their insular status, and some important differences between insular and continental populations have been described (e.g. [ ] ). thus, our study adds new important insights into the dispersal behavior of m. nattereri in mainland europe. moreover, we investigated for the first time if genetic covariation occurs between populations of a bat host and its harboured astroviruses. fischer et al. [ ] reported distinctly higher similarities in astrovirus sequences of samples collected from the same bat species in different geographic localities than between samples from different species sampled at the same locality, whereas different results were obtained in the czech republic for some other european bat species [ ] . because our analyses are based on the sequences found by fischer et al. [ ] in m. nattereri, we assume that, similarly to coronaviruses in chinese bats [ ] , astroviruses are mostly transmitted within natterer's bats rather than within the local bat community as a whole. we hypothesized that if virus transmission between host populations were associated with events linked to gene flow in the bats, e.g. mating [ ] , genetic co-variation should be detectable between host populations and astroviruses on a larger scale (e.g. between geographic regions), even though not necessarily within a certain region. many bat astroviruses form distinct phylogenetic clusters [ ] , but little is known whether astrovirus population structure matches that of their host species. as astroviruses are hypothesized to be transmitted via the fecal-oral route [ ] , both direct and indirect virus transmission within the breeding colonies of bats and at swarming sites during mating seem possible [ ] . in comparison, for bat ectoparasites such as bat flies (nycteribiidae) that are also transmitted both by direct body contact and indirectly through the bats' roosts, a more efficient transmission among different bat populations has been detected at swarming sites as compared to breeding colonies [ ] . as swarming sites represent the main mating sites for m. nattereri, where gene flow occurs, it is expected that if viruses are also mainly transmitted between conspecifics during that period, the transmission route of the viruses should resemble the pattern of host gene flow. since transmission of astroviruses at swarming sites would cause viruses to be transmitted between members of different colonies visiting a given swarming site, local differentiation should not occur at the colony level but rather on a larger scale. viral genetic patterns should therefore follow an isolation-by-distance pattern using swarming sites as stepping-stones for gene flow, as suggested for the bat host [ ] . sampling occurred between and from maternity colonies in three regions in germany: bavaria (by, n = adult females, one colony), north rhine westphalia (nrw, n = adult females, five colonies) and mecklenburg western pomerania (mv, n = adult females, ten colonies; fig. ). bats were either taken directly out of the bat boxes provided for the colonies or captured using mist nets or harp traps when leaving the colonies' roosts. three millimeter wing tissue samples were collected and stored in % ethanol until dna extraction. in addition, between and , samples of bat saliva, feces and urine were opportunistically taken within the three regions of interest (by, n = ; nrw, n = ; mv, n = ) and screened for the presence of astrovirus-related rna (additional file : table s ). genomic dna was extracted using an ammonium acetate precipitation method [ ] . individuals were genotyped using nuclear microsatellite markers and one mitochondrial microsatellite marker. the following nuclear markers were used: ef [ ] ; b [ ] ; a -mluc, a -mluc, e -mluc, g -mluc, g -mluc, g -mluc [ ] , d , h , h , h [ ] ; mnatt- , mnatt- [ ] ; mschreib [ ] ; mnatt- , mnatt- [ ] ; fv ap [ ] and gzbyr ( ′-tccttgtcactataagctcagtgg- ′ (forward); ′-ccaggcaatagtctcctagcac- ′ (reverse)). the ′ end of the reverse primers fv ap and g -mluc were pig-tailed [ ] with the sequence gttt and the ′ end of the reverse primer g -mluc with the sequence gtttt to facilitate adenylation. these autosomal microsatellite markers were amplified in two multiplex polymerase chain reactions (pcrs, table ). pcrs were carried out in μl reaction volumes using the qiagen multiplex kit (qiagen, hilden, germany). each multiplex reaction contained x qiagen multiplex master mix and between . μm and . μm of each primer. after drying μl of dna (approximately ng) for min at °c in a -well pcr plate (vwr), multiplex reactions were performed. the pcr amplification was carried out in a thermal cycler (applied biosystems), with an initial min denaturation at °c, followed by cycles with denaturation at °c for s, annealing at °c for s and extension at °c for min. final incubation occurred at °c for min. the mitochondrial dna marker at- [ ] was amplified in a separate pcr. after drying μl of dna (approximately ng) for min at °c in a -well pcr plate (vwr), this pcr was carried out in μl reaction volume which contained . μm of primer at- , . mm dntps, . mm of mgcl , . μl x taq buffer b (solis, biodyne, tartu, estonia) and unit of taq hot firepol® dna polymerase (solis, biodyne, tartu, estonia). this pcr amplification was carried out in a thermal cycler (applied biosystems), with an as in by only one colony was sampled, no close-up is provided initial min denaturation at °c, followed by cycles with denaturation at °c for s, annealing at °c for s and extension at °c for min. final incubation occurred at °c for min. pcr products were separated using an abi genetic analyzer (applied biosystems) together with the internal size standard genescan liz (applied biosystems) and analyzed using genemapper v . (applied biosystems). since it has been reported that the presence of closely related individuals within populations can bias bayesian multi-locus clustering methods [ ] , we removed closely related individuals from the dataset before conducting population genetic structure analyses using the program structure [ ] . for this purpose, we first determined the degree of relatedness between all pairs of individuals within a population using trioml [ ] , as implemented in the coancestry . . . software package [ ] . relatedness densities were further plotted using r (r core [ ] ) in order to determine the relatedness threshold for excluding individuals from the analyses. this threshold was selected manually by best separating the first peak of the plotted distribution (i.e. closely related individuals) from the rest (unrelated individuals). from every pair of individuals with a relatedness value exceeding the determined threshold ( . ), one individual was randomly removed, respectively. all other analyses, except for structure, were performed on the whole data set. as uneven sampling can bias inferences on the number of clusters in the program structure [ ] , efforts were made to have comparable number of individuals from the three regions investigated after the removal of closely related individuals ( from by, from nrw and from mv; cf. results). as preliminary runs using the original structure model showed limited population structure (additional file : figure s ), structure [ ] was run on the nuclear dna dataset assuming admixture and correlated allele frequencies using the locprior model that allows for the use of sample group information (here the colony) in the clustering process [ ] . thus, twenty independent runs of k = - were conducted for the whole dataset after removing closely related individuals as mentioned above. additionally, twenty independent runs of k = - were run for each dataset within a sampling region (nrw, mv and by), respectively. all runs used iterations after a burn-in period of . for each of the genetically distinct populations inferred by structure the significance of deviations from hardy-weinberg equilibrium (hwg, [ ] ) and linkage disequilibrium between loci was tested in genepop . . [ ] . the false discovery rate (fdr) correction method was used to deal with multiple testing [ ] . to assess the level of genetic diversity, the observed (h o ) and expected heterozygosity (h ex ) for each locus as well as for each population inferred by structure for the complete data set were calculated using genetix . . [ ] . the mean number of alleles (a) and the allelic richness (a r ) were calculated for each locus and each subpopulation using fstat v. . . [ ] (table ) . differences in the number of alleles per locus, allelic richness and expected and observed heterozygosities between the populations inferred by structure were tested for significance using the wilcoxon signed-rank test in r. micro-checker . . [ ] , set for iterations and a % confidence interval, was used to test for null alleles. population pairwise f st values [ ] on the whole dataset including closely related individuals, were used to measure the level of genetic differentiation between the populations inferred by structure. for both the nuclear and the mitochondrial dna data set, a hierarchical population structure was assumed where colonies were clustered within regions. f st values were thus calculated using hierarchical analyses within the r-package hierfstat [ , ] . genetic structure was tested among colonies within sampling regions with more than colony (mv and nrw) and among sampling regions. the significance of the f-statistics was tested by , permutations. isolation-by-distance for the entire set of colonies was tested via mantel's test [ ] from the comparison of all pairwise f st /( -f st ) values with pairwise geographic distances using the r package ecodist [ ] with , permutations. the test was performed for the whole dataset as well as within regions consisting of several colonies (nrw and mv). a total of samples obtained from saliva, feces and urine of myotis nattereri were screened for the presence of astroviruses by using a published hemi-nested pcr protocol [ ] for the amplification of a highly conserved region of the rna dependent rna polymerase gene (rdrp). this pcr assay enables the detection of a variety of bat-associated astroviruses by using degenerated primers. further details of the virus-related sampling and laboratory are presented in fischer et al. [ ] . a total sequences representing different astrovirus haplotypes (=sequences having % identity) (n - , fig. ) were identified from the screening of samples. three haplotypes were excluded from the analyses (n - , fig. ) as they were phylogenetically too distant from the remaining and too rarely encountered (only once per haplotype) to make biologically meaningful inferences about their correlation to the bat host's population genetic structure. out of the samples, fischer et al. [ ] were able to assign individual sequences to a specific haplotype (n - , fig. ) , whereas the remaining astrovirus positive samples were shorter than nt and could therefore not be assigned to a haplotype. as in this study we only analyzed individually marked adult female bats that were clearly identifiable via their rfid-tag, in total individual sequences, representing these different haplotypes, were used (n - , fig. ) . the genetic distances between the different astrovirus haplotypes were calculated using the tamura-nei model implemented in mega . [ ] . further, the sequences were translated into amino acids and amino acid genetic distances were computed using the p-dist method implemented in mega . [ ] . this latter measure was tentatively used to differentiate viral species following the recommendation of the astroviridae working group of the international committee for taxonomy of viruses (ictv astroviridae working [ ] ), proposing that mean amino acid genetic distances (p-dist) of the full length orf larger than . distinguish different species. as we found no shared identical sequences between regions (by, mv and nrw), a permutation test was conducted using r (r core [ ] ) to test how likely such a pattern would be expected by chance (additional file : database s ). moreover, the program poptree [ ] was used to generate genetic distance matrices for the nuclear and mitochondrial dna datasets based on the d a distances [ ] of population microsatellite allele frequencies within a priori populations. for the astrovirus dataset, we first used the program jmodeltest . . [ ] to calculate likelihood scores for substitution model selection. genetic and amino acid distances were then calculated using mega . [ ] based on the maximum composite likelihood substitution model with gamma correction for among-site rate heterogeneity and an estimated proportion of invariable sites. associations between astrovirus and bat host genetic distances (both mitochondrial and nuclear) were first analyzed via a mantel test [ ] using the software genalex . [ ] . to control for the possible effect of geographic distance, we also carried out partial mantel tests in passage v . . . ( permutations, [ ] ). the geographic distance matrix used was calculated from the gps coordinates of the different sampling sites using the create option in passage. for the genetic correlations between host and astrovirus sequences the nrw dataset was modified. due to significant population genetic structuring on the basis of mtdna and the fact that the sampled colonies in nrw are up to km apart from each other compared to maximally . km in mv (see fig. ) we split the nrw data set in four separate sampling units (nrw , nrw , nrw and nrw ; fig. ). here, we only used genetic data from the colonies within nrw where virus sequences were detected. together with mv and by, the total dataset for comparing host and virus population structures now consisted of six populations between which pairwise genetic distances were computed as mentioned above. after removing closely related individuals at the threshold of . , the nuclear dna dataset consisted of samples from bats in total, including from by, from nrw and from mv. using the autosomal microsatellite loci, structure inferred the presence of three distinct genetic clusters ( fig. ; additional file : figure s ), splitting our data set into the three sampled regions nrw, mv and by. no additional sub-structuring was detected by structure within any of these three sampling regions (data not shown). the autosomal microsatellite loci had between and alleles and an average of . - . alleles per each of the three genetically distinct populations inferred by the program structure (table ) . no significant deviations from hardy-weinberg equilibrium were detected in these three populations. deviations from linkage disequilibrium at the α = . level (after fdr correction) did occur consistently in all three regions between two loci (mnatt- and mnatt- , table ) but were not detected in all respective colonies (linkage occurred in by, in three out of ten colonies in mv and in three out of five colonies in nrw). because of the inconsistencies at the colony level, we decided to nevertheless keep both loci for further analyses. no marker with consistently appearing null alleles was found within nrw and mv, whereas in by the two loci ef and fv ap showed the presence of null alleles. however, since the estimated frequency of null alleles per locus was low (< . ), we kept those loci. mean expected and observed heterozygosity were globally similar across colonies and regions (tables and ). the number of alleles found in mv was significantly higher than in by (p = . ) and nrw (p = . ), but by and nrw did not differ significantly from each other. moreover, allelic richness was significantly higher in mv as compared to by (p = . ) but no significant differences were found between by and nrw and between nrw and mv. the overall level of differentiation among the three regions was weak but significant (f st = . , p = . ) based on nuclear dna estimated using hierarchical f-statistics. significant genetic differentiation was further identified among colonies within regions (f st = . , p = . ). when analyzing the data obtained by the mitochondrial dna marker at- , pairwise genetic differentiation was found to be much higher at both geographic scales (among regions: f st = . , p = . ; among colonies within regions: f st = . , p = . ). when correlating genetic differentiation f st /( -f st ) with ln of geographic distances between all colonies within our study area, a significant pattern of isolationby-distance was detected (mantel r = . , p = . ; fig. ). in contrast, the isolation-by-distance patterns within the nrw (mantel r = - . , p = . ) and the mv population (mantel r = . , p = . ) were not significant, even though in mv there was a similar trend visible as in the entire data set. we found no overlap in the detected haplotypes between the three regions (fig. ) . the permutation test revealed that the probability of having no such overlap by chance was very low (p = . ; , permutations). however, a closer look at the genetic relationship of the different astrovirus haplotypes (fig. ) revealed that sequences of high similarity occur in different geographic regions. genetic distances in astrovirus haplotypes that cluster together (n - , n - , n - , n - , n - ; fig. ) ranged between . and . , whereas genetic distances among clusters were distinctly higher ( . - . ). as for the amino acid genetic distances (p-dist), distances ranged between . - . and . - . within and between clusters, respectively, the latter being typical of species differences. rough estimations of divergence times using an astrovirus mutation rate of × − [ ] indicate that differences within clusters have occurred within - years, versus - years for between-cluster divergence time. furthermore, the astrovirus genetic distances neither correlated with those of the host's nuclear dna nor with those of the host's mitochondrial dna. this was true both for the mantel tests and for the partial mantel test correcting for geographic distance (table ). in this study, we analyzed the population genetic structure of m. nattereri within and among summer colonies at different geographical scales in germany and correlated it with that of the astrovirus sequences found in the respective host colonies. our aim was to assess whether the population structure and dispersal patterns of host populations can explain the genetic structure of astrovirus sequences and thus ultimately shed light on the virus transmission dynamics within a given bat species [ , ] . our findings show significant population structure in m. nattereri with the detection of three genetic clusters which correspond to the three regions sampled (nrw, mv and by). both the results obtained using the bayesian clustering approach and the f st values between the three genetic clusters show the existence of significant population genetic structure. the detection of an isolation-by-distance pattern over the whole study area combined with the continuous presence of the species across germany suggests that the levels of gene flow are not high enough to prevent some population differentiation [ ] . the observed strong mitochondrial substructure and weak but significant structure at the nuclear level, likely results from differences in effective population size and female philopatry combined with male-mediated gene flow. differences in patterns of genetic structure in mitochondrial and nuclear dna have been reported in many european bat species and were associated with male-biased dispersal [ , ] . according to previous studies in m. nattereri in the uk [ , ] , both sexes fig. isolation-by-distance analysis for data from nuclear microsatellite loci from myotis nattereri within germany. the graph displays the significant correlation between genetic differentiation and ln of geographical distance (in km) for all pairwise comparisons of colonies. genetic distance was measured as rousset's f st /( -f st ) and the relationship with geographic distance was tested using a mantel test with permutations. the line represents a linear regression of this relationship and only serves an illustrative purpose appear to be highly philopatric to their natal area but visit central swarming sites during autumn for mating. according to rivers et al. [ ] , this pattern results in the same genetic pattern as permanent male dispersal [ ] . in connection with the existing overall population isolation-by-distance pattern detected and the absence of a significant pattern on a local scale, i.e. within a region, we suggest that individuals from different summer colonies meet and mate at swarming sites within each region (e.g. [ , ] ). this would result in gene flow following a stepping-stone model and would both lead to a significant isolation-by-distance over larger scales [ ] and to the absence or a weak signal on a local scale [ , ] . within the uk, isolation-by-distance was not detected between summer colonies of m. nattereri unless distances exceeded km [ ] . our results agree with those obtained by rivers et al. [ ] as we also did not detect significant genetic isolation-by-distance between summer colonies within a given region in germany (even though there is a trend in mv), but over the study area as a whole. therefore, we suggest that the isolation-by-distance pattern observed here is generated by swarming sites acting as stepping-stones for gene flow. in our study area, identical astrovirus haplotypes harbored by m. nattereri do not overlap between geographic regions (by, mv and nrw, fig. ). based on the partial sequence of the conserved rdrp gene analysed in this study [ ] , where the mean amino acid distances ranged from . to . within and . - . between clusters, the analyzed haplotypes form six different groups which might represent six different viral species [ ] (c - , fig. ). the detection of the same putative viral species in the different regions combined with the estimated divergence times (< years for within species) suggests occasional transmission between host populations. both the observed genetic population structure of m. nattereri and existing data from ringing studies in germany [ ] show that natterer's bats rarely if ever move over long distances (more than km). thus, it is unlikely that individual bats directly transmit a certain virus haplotype between the three geographic regions analyzed (nrw, by and mv). since viruses have a considerably higher mutation rate [ ] compared to the bat host, mutations in the virus sequences do occur within much shorter time scales than mutation in the bats' genome [ , ] . as bats need to transmit the astroviruses directly, the movement of viruses across the landscape should mirror the movement of the bats and hence occur successively over large distances following the stepping stone model of the host. as a consequence, virus transmission over large distances is likely to take multiple years. in the course of these successive transmissions events, mutations will occur in the virus which will lead to viral population differentiation as we observe within the putative viral species. no association was found when correlating the genetic distances of the different astrovirus sequences with their bat host genetic distances. we had originally expected that if the transmission route of astrovirus sequences resembles the pattern of host gene flow, genetic covariation between astroviruses and host populations should be detected, especially across regions. the reason why no such correlation was found for m. nattereri and its associated astroviruses could be due to strong differences in population size (hence genetic drift) and mutation rate between bats and viruses. in contrast to higher eukaryotes such as the bat host, rna viruses are subject to higher selective pressures and combined with a high mutation rate allow continuous and rapid adaptation to changing environmental conditions [ , , ] . coupled with large population sizes, virus evolution can thus already be observed within very short time scales of weeks to months [ , ] . the frequent fluctuations in the prevalence of viral populations (e.g. bottlenecks) and hence the higher genetic drift they face might prevent these populations from showing patterns of isolation-bydistance [ ] . moreover, our virus sampling could only be performed during the summer period since only some of the autumn swarming sites are known so far. additionally, due to logistic reasons exact sampling dates differed between the sampling localities, which could blur the signal if some haplotypes or putative viral species are more abundant in different periods (see additional file : table s ). finally, although large from a virology perspective, the number of samples with viral material was relatively limited to perform population genetics analyses. this combined with the variations in sampling times could confound our analysis if viruses show quick temporal variation in prevalence and/or turnover. a further possible explanation for the lack of a genetic correlation between hosts and viruses is that at swarming sites bats may not only interact in ways that lead to gene flow. multiple mating and contact between individuals that does not result in successful mating might also represent transmission opportunities for viruses that are not reflected within the host genetic pattern. in summary, our findings suggest that for m. nattereri within germany, swarming sites act as steppingstones for gene flow, as indicated by an overall isolation-by-distance pattern and the absence of such a significant pattern on a local scale. the observed population genetic structure indicates that no apparent strong barriers to gene flow exist within our study area for the bat host. while putative viral species were mostly shared between geographic regions, no haplotypes were shared for any putative viral species. despite the observed genetic differentiation between the three geographic regions in the bat host and to a certain extent also in the harbored astroviruses, we did not detect a correlation between host and virus genetic distances. this could potentially be due to differences in genetic drift, selective pressure, population size and mutation rate between bats and viruses. further studies with a higher astrovirus sample size and with specific simultaneous sampling during autumn mating at swarming sites are required to shed further light on the host-virus relationship between bats and their astroviruses. additional file : supplementary material. figure s . summary of the log-likelihood values from the independent runs conducted with structure for the number of genetic clusters (k) set to a minimum of and a maximum of . the left graph shows the log-likelihood results of the runs for each k, whereas the right graph shows delta k plotted against k. the most likely number of genetic clusters is three using both methods. figure s . comparisons of the structure runs for k = with (top) or without (bottom) the locprior option. table s . 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pairwise relatedness coancestry: a program for simulating, estimating and analysing relatedness and inbreeding coefficients team rc: r: a language and environment for statistical computing. r foundation for statistical computing the program structure does not reliably recover the correct population structure when sampling is uneven: subsampling and new estimators alleviate the problem inferring weak population structure with the assistance of sample group information estimation of average heterozygosity and genetic distance from a small number of individuals genepop (version- . ) -population-genetics software for exact tests and ecumenicism controlling the false discovery rate -a practical and powerful approach to multiple testing genetix . , logiciel sous windows pour la génétique des populations. france: laboratoire génome populations interactions fstat (version . ): a computer program to calculate f-statistics micro-checker: software for identifying and correcting genotyping errors in microsatellite data the genetical structure of populations hierfstat, a package for r to compute and test hierarchical f-statistics a step-by-step tutorial to use hierfstat to analyse populations hierarchically structured at multiple levels the detection of disease clustering and a generalized regression approach the ecodist package for dissimilarity-based analysis of ecological data mega : molecular evolutionary genetics analysis version . group iaw. ictv official taxonomy: updates since the th report poptree : software for constructing population trees from allele frequency data and computing other population statistics with windows interface accuracy of extimated phylogenetic trees from molecular data, ii. gene-frequency data phylogenetic model averaging genalex . : genetic analysis in excel. population genetic software for teaching and research-an update passage: pattern analysis, spatial statistics and geographic exegesis. version high evolutionary rate of human astrovirus using spatial bayesian methods to determine the genetic structure of a continuously distributed population: clusters or isolation by distance? contrasted patterns of mitochondrial and nuclear structure among nursery colonies of the bat myotis myotis high gene diversity at swarming sites suggest hot spots for gene flow in the endangered bechstein's bat the stepping stone model of population structure and the decrease of genetic correlation with distance jahre fledermausmarkierungszentrale dresden: methodische hinweise und ergebnisübersicht: saxoprint different rates of (non-)synonymous mutations in astrovirus genes; correlation with gene function rna virus mutations and fitness for survival models of rna virus evolution and their roles in vaccine design future issues in rna virus evolution rates of spontaneous mutation correlation of pairwise genetic and geographic distance measures: inferring the relative influences of gene flow and drift on the distribution of genetic variability we thank the local forestry and conservation departments as well as the "fledermausforschungsprojekt wooster teerofen e.v." for support and the following people for help in the field: daniela fleischmann, lena grosche, ralf koch, markus melber, and jaap van schaik. for general support during the lab work we thank ina römer, and katja böhm and franziska neitzel who helped to design the primers fv ap and gzbyr. we are grateful to stefan braendel, kathleen drescher, nicola fischer, alain frantz, darren obbard, jaap van schaik, caroline schöner, eric witt and one anonymous referee for providing comments on the manuscript. this work was funded by the deutsche forschungsgemeinschaft (ke / - and ke / - ) within the priority programm "ecology and species barriers in emerging viral diseases (spp )". the datasets supporting the conclusions of this article are included within the article (and its additional files and ). the genbank accession numbers for the astrovirus sequences detected to be harboured by m. nattereri are kt -kt . authors' contributions th and gk designed the study with input from ab-b, sjp and kf. gk, vz, fm and ct provided samples. th and rg performed the laboratory work. th performed data analyses on bats and viral sequences and drafted the manuscript with input from ab-b, kf, sjp and gk. sjp contributed to analysis. all authors have commented on the manuscript, read and approved the final version of the manuscript. the authors declare that they have no competing interests. submit your next manuscript to biomed central and we will help you at every step: key: cord- -ron oqrn authors: afshordi, niayesh; holder, benjamin; bahrami, mohammad; lichtblau, daniel title: diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states date: - - journal: nan doi: nan sha: doc_id: cord_uid: ron oqrn the sars-cov- pandemic has caused significant mortality and morbidity worldwide, sparing almost no community. as the disease will likely remain a threat for years to come, an understanding of the precise influences of human demographics and settlement, as well as the dynamic factors of climate, susceptible depletion, and intervention, on the spread of localized epidemics will be vital for mounting an effective response. we consider the entire set of local epidemics in the united states; a broad selection of demographic, population density, and climate factors; and local mobility data, tracking social distancing interventions, to determine the key factors driving the spread and containment of the virus. assuming first a linear model for the rate of exponential growth (or decay) in cases/mortality, we find that population-weighted density, humidity, and median age dominate the dynamics of growth and decline, once interventions are accounted for. a focus on distinct metropolitan areas suggests that some locales benefited from the timing of a nearly simultaneous nationwide shutdown, and/or the regional climate conditions in mid-march; while others suffered significant outbreaks prior to intervention. using a first-principles model of the infection spread, we then develop predictions for the impact of the relaxation of social distancing and local climate conditions. a few regions, where a significant fraction of the population was infected, show evidence that the epidemic has partially resolved via depletion of the susceptible population (i.e.,"herd immunity"), while most regions in the united states remain overwhelmingly susceptible. these results will be important for optimal management of intervention strategies, which can be facilitated using our online dashboard. the new human coronavirus sars-cov- emerged in wuhan province, china in december (chen et al., ; li et al., ) , reaching , confirmed cases and deaths due to the disease (known as by the end of january this year. although travel from china was halted by late-january, dozens of known introductions of the virus to north america occurred prior to that (holshue et al., ; kucharski et al., ) , and dozens more known cases were imported to the us and canada during february from europe, the middle east, and elsewhere. community transmission of unknown origin was first detected in california on february , followed quickly by washington state (chu et al., b) , illinois and florida, but only on march in new york city. retrospective genomic analyses have demonstrated that case-tracing and self-quarantine efforts were effective in preventing most known imported cases from propagating (ladner et al., ; gonzalez-reiche et al., ; worobey et al., ) , but that the eventual outbreaks on the west coast (worobey et al., ; chu et al., b; deng et al., ) and new york (gonzalez-reiche et al., ) were likely seeded by unknown imports in mid-february. by early march, cross-country spread was primarily due to interstate travel rather than international imports (fauver et al., ) . in mid-march , nearly every region of the country saw a period of uniform exponential growth in daily confirmed cases -signifying robust community transmission -followed by a plateau in late march, likely due to social mobility reduction. the same qualitative dynamics were seen in covid- mortality counts, delayed by approximately one week. although the qualitative picture was similar across locales, the quantitative aspects of localized epidemics -including initial rate of growth, infections/deaths per capita, duration of plateau, and rapidity of resolution -were quite diverse across the country. understanding the origins of this diversity will be key to predicting how the relaxation of social distancing, annual changes in weather, and static local demographic/population characteristics will affect the resolution of the first wave of cases, and will drive coming waves, prior to the availability of a vaccine. the exponential growth rate of a spreading epidemic is dependent on the biological features of the virus-host ecosystem -including the incubation time, susceptibility of target cells to infection, and persistence of the virus particle outside of the host -but, through its de-pendence on the transmission rate between hosts, it is also a function of external factors such as population density, air humidity, and the fraction of hosts that are susceptible. initial studies have shown that sars-cov- has a larger rate of exponential growth (or, alternatively, a lower doubling time of cases ) than many other circulating human viruses (park et al., ) . for comparison, the pandemic influenza of , which also met a largely immunologically-naive population, had a doubling time of - d (yu et al., ; storms et al., ) , while that of sars-cov- has been estimated at - d (sanche et al., ; oliveiros et al., ) (growth rates of ∼ . d − vs. ∼ . d − ). it is not yet understood which factors contribute to this high level of infectiousness. while the dynamics of an epidemic (e.g., cases over time) must be described by numerical solutions to nonlinear models, the exponential growth rate, λ, usually has a simpler dependence on external factors. unlike case or mortality incidence numbers, the growth rate does not scale with population size. it is a directly measurable quantity from the available incidence data, unlike, e.g., the reproduction number, which requires knowledge of the serial interval distribution (wallinga and lipsitch, ; roberts and heesterbeek, ; dushoff and park, ) , something that is difficult to determine empirically (champredon and dushoff, ; nishiura, ). yet, the growth rate contains the same threshold as the reproduction number (λ = vs. r = ), between a spreading epidemic (or an unstable uninfected equilibrium) and a contracting one (or an equilibrium that is resistant to flare-ups). thus, the growth rate is an informative direct measure on that space of underlying parameters. in this work, we leverage the enormous data set of epidemics across the united states to evaluate the impact of demographics, population density and structure, weather, and non-pharmaceutical interventions (i.e., mobility restrictions) on the exponential rate of growth of covid- . following a brief analysis of the initial spread in metropolitan regions, we expand the meaning of the exponential rate to encompass all aspects of a local epidemic -including growth, plateau and decline -and use it as a tracer of the dynamics, where its time dependence and geographic variation are dictated solely by these external variables and per capita cumulative mortality. finally, we use the results of that linear analysis to calibrate a new nonlinear model -a renewal equation that utilizes the excursion probability of a random walk to determine the incubation period -from which we develop local predictions about the impact of social mobility relaxation, the level of herd immunity, and the potential of rebound epidemics in the summer and fall. diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states initial growth of cases in metropolitan regions is exponential with rate depending on mobility, population, demographics, and humidity as an initial look at covid- 's arrival in the united states, we considered the ∼ most populous metropolitan regions -using maps of population density to select compact sets of counties representing each region (see supplementary material) -and estimated the initial exponential growth rate of cases in each region. we performed a linear regression to a large set of demographic (sex, age, race) and population variables, along with weather and social mobility (fitzpatrick and karen, ) preceding the period of growth ( figure ). in the best fit model (r = . , bic = − ), the baseline value of the initial growth rate was λ = . d − (doubling time of . d), with average mobility two weeks prior to growth being the most significant factor ( figure b ). of all variables considered, only four others were significant: population density (including both populationweighted density (pwd) -also called the "lived population density" because it estimates the density for the average individual (craig, ) -and population sparsity, γ, a measure of the difference between pwd and standard population density, see methods), p < . and p = . ; specific humidity two weeks prior to growth, p = . ; and median age, p = . . while mobility reduction certainly caused the "flattening" of case incidence in every region by late-march, our results show ( figure c ) that it likely played a key role in reducing the rate of growth in boston, washington, dc, and los angeles, but was too late, with respect to the sudden appearance of the epidemic, to have such an effect in, e.g., detroit and cleveland. in the most extreme example, grand rapids, mi, seems to have benefited from a late arriving epidemic, such that its growth (with a long doubling time of d) occurred almost entirely post-lockdown. specific humidity, a measure of absolute humidity, has been previously shown to be inversely correlated with respiratory virus transmission (lowen et al., ; shaman and kohn, ; shaman, goldstein, and lipsitch, ; kudo et al., ) . here, we found it to be a significant factor, but weaker than population density and mobility ( figure c ). it could be argued that dallas, los angeles, and atlanta saw a small benefit from higher humidity at the time of the epidemic's arrival, while the dry latewinter conditions in the midwest and northeast were more favorable to rapid transmission of sars-cov- . in the remainder of this report, we consider the exponential rate of growth (or decay) in local confirmed deaths due to covid- . the statistics of mortality is poorer compared to reported cases, but it is much less dependent on unknown factors such as the criteria for testing, local policies, test kit availability, and asymptomatic individuals (pearce et al., ) . although there is clear evidence that a large fraction of covid- mortality is missed in the official counts (e.g., leon et al., ; modi et al., ) , mortality is likely less susceptible to rapid changes in reporting, and, as long as the number of reported deaths is a monotonic function of the actual number of deaths (e.g., a constant fraction, say %), the sign of the exponential growth rate will be unchanged, which is the crucial measure of the success in pandemic management. to minimize the impact of weekly changes, such as weekend reporting lulls, data dumps, and mobility changes from working days to weekends, we calculate the regression of ln [mortality] over a -day interval, and assign this value, λ (t), and its standard error to the last day of the interval. since only the data for distinct -week periods are independent, we multiply the regression errors by √ to account for correlations between the daily estimates. together with a "rolling average" of the mortality, this time-dependent measure of the exponential growth rate provides, at any day, the most up-to-date information on the progression of the epidemic (figure ). in the following section, we consider a linear fit to λ , to determine the statistically-significant external (non-biological) factors influencing the dynamics of local exponential growth and decline of the epidemic. we then develop a first-principles model for λ that allows for extrapolation of these dependencies to predict the impact of future changes in social mobility and climate. epidemic mortality data explained by mobility, population, demographics, depletion of susceptible population and weather, throughout the first wave of covid- we considered a spatio-temporal dataset containing estimates of the exponential growth measure, λ , covering the three month period of march - june in the us counties for which information on covid- mortality and all potential driving factors, below, were available (the main barrier was social mobility information, which limited us to a set of counties that included % of us mortality). a joint, simultaneous, diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states linear fit of these data to potential driving factors (table ) revealed only factors with independent statistical significance. re-fitting only to these variables returned the optimal fit for the considered factors (bic = − ; r = . ). we found, not surprisingly, that higher population density, median age, and social mobility correlated with positive exponential growth, while population sparsity, specific humidity, and susceptible depletion correlated with exponentially declining mortality. notably the coefficients for each of these quantities was in the % confidence intervals of those found in the analysis of metropolitan regions (and vice versa). possibly the most surprising dependency was the negative correlation, at − . σ between λ and the total number of annual deaths in the county. in fact, this correlation was marginally more significant than a correlation with log(population), which was − . σ. one possible interpretation of this negative correlation is that the number of annual death is a proxy for the number of potential outbreak clusters. the larger the number of clusters, the longer it might take for the epidemic to spread across their network, which would (at least initially) slow down the onset of the epidemic. to obtain more predictive results, we developed a mechanistic nonlinear model for infection (see supplementary material for details). we followed the standard analogy to chemical reaction kinetics (infection rate is proportional to the product of susceptible and infectious densities), but defined the generation interval (approximately the incubation period) through the excursion probability in a d random walk, modulated by an exponential rate of exit from the infected class. this approach resulted in a renewal equation (heesterbeek and dietz, ; champredon and dushoff, ; champredon, dushoff, and earn, ) , with a distribution of generation intervals that is more realistic than that of standard sir/seir models, and which could be solved formally (in terms of the lambert w function) for the growth rate in terms of the infection parameters: the model has four key dependencies, which we describe here, along with our assumptions about their own dependence on population, demographic, and climate variables. as mortality (on which our estimate of growth rate is based) lags infection (on which the renewal equation is based), we imposed a fixed time shift of ∆t for timedependent variables: . we assumed that the susceptible population, which feeds new infections and drives the growth, is actually a sub-population of the community, consisting of highly-mobile and frequently interacting individuals, and that most deaths occurred in separate subpopulation of largely immobile non-interacting individuals. under these assumptions, we found (see supp. mat.) that the susceptible density, s(t), could be estimated from the cumulative per capita death fraction, f d , as: where d tot is the cumulative mortality count, n is the initial population, and the initial density is s( ) = k pwd. . we assumed that the logarithm of the "rate constant" for infection, β, depended linearly on social mobility, m, specific humidity, h, population sparsity, γ, and total annual death, a d , as: where a barred variable represents the (populationweighted) average value over all us counties, and where the mobility and humidity factors were timeshifted with respect to the growth rate estimation window: m = m (t − ∆t) and h = h (t − ∆t). . the characteristic time scale to infectiousness, τ , is intrinsic to the biology and therefore we assumed it would depend only on the median age of the population, a. we assumed a power law dependence: where we fixed the pivot age, a , to minimize the error in τ . . the exponential rate of exit from the infected class, d, was assumed constant, since we found no significant dependence for it on other factors in our analysis of us mortality. from the properties of the lambert w function, when the infection rate or susceptibility density approach zero -through mobility restrictions or susceptible depletion -the growth rate will tend to λ ≈ −d, its minimum value. with these parameterizations, we performed a nonlinear regression to λ (t) using the entire set of us county mortality incidence time series (table ). compared to the linear model of the previous section (table b) diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states individual's probability of becoming infectious, and the distributions of incubation period and generation interval, all as a function of the median age of the population (see supplementary material). the model was very well fit to the mortality growth rate measurements for counties with a high mortality ( figure ). more quantitatively, the scatter of measured growth rates around the best-fit model predictions was (on average) only % larger than the measurement errors, independent of the population of the county . importantly, when the model was calibrated on only a subset of the data -e.g., all but the final month for which mobility data is available -its % confidence prediction for the remaining data was accurate (figure ) given the known mobility and weather data for that final month. this suggests that the model, once calibrated on the first wave of covid- infections, can make reliable predictions about the ongoing epidemic, and future waves, in the united states. possibly the most pressing question for the management of covid- in a particular community is the combination of circumstances at which the virus fails to propagate, i.e., at which the growth rate, estimated here by λ , becomes negative (or, equivalently, the reproduction number r t falls below one). in the absence of mobility restrictions this is informally called the threshold for "herd immunity," which is usually achieved by mass vaccination (e.g., john and samuel, ; fine, eames, and heymann, ) . without a vaccine, however, ongoing infections and death will deplete the susceptible population and thus decrease transmission. varying the parameters of the nonlinear model individually about their spring population-weighted mean values ( figure ) suggests that this threshold will be very much dependent on the specific demographics, geography, and weather in the community, but it also shows that reductions in social mobility can significantly reduce transmission prior the onset of herd immunity. to determine the threshold for herd immunity in the absence or presence of social mobility restrictions, we considered the "average us county" (i.e., a region with population-weighted average characteristics), and examined the dependence of the growth rate on the cumulative mortality. we found that in the absence of social distancing, a covid- mortality rate of . % (or per million population) would bring the growth rate to zero. however, changing the population density of this average county shows that the threshold can vary widely ( figure ). examination of specific counties showed that the mortality level corresponding to herd immunity varies from to per million people (figure ). at the current levels of reported covid- mortality, we found that, as of june nd, , only ± out of counties (inhabiting . ± . % of us population) have surpassed this threshold at % confidence level ( figure ). notably, new york city, with the highest reported per capita mortality ( per million) has achieved mobility-independent herd immunity at the σ confidence level, according to the model ( figure ). a few other large-population counties in new england, new jersey, michigan, louisiana, georgia and mississippi that have been hard hit by the pandemic also appear to be at or close to the herd immunity threshold. this is not the case for most of the united states, however ( figure ). nationwide, we predict that covid- herd immunity would only occur after a death toll of , ± , , or ± per million of population. we found that the approach to the herd immunity threshold is not direct, and that social mobility restrictions and other non-pharmaceutical interventions must be applied carefully to avoid excess mortality beyond the threshold. in the absence of social distancing interventions, a typical epidemic will "overshoot" the herd immunity limit (e.g., handel, longini jr, and antia, ; fung, antia, and handel, ) by up to %, due to ongoing infections ( figure ). at the other extreme, a very strict "shelter in place" order would simply delay the onset of the epidemic; but if lifted (see figures and ), the epidemic would again overshoot the herd immunity threshold. a modest level of social distancing, however -e.g., a % mobility reduction for the average us county -could lead to fatalities "only" at the level of herd immunity. naturally, communities with higher population density or other risk factors (see figure ), would require more extreme measures to achieve the same. avoiding the level of mortality required for herd immunity will require long-lasting and effective nonpharmaceutical options, until a vaccine is available. the universal use of face masks has been suggested for reducing the transmission of sars-cov- , with a recent meta-analysis (chu et al., a) suggesting that masks can suppress the rate of infection by a factor of . - . ( % ci), or equivalently ∆ ln(transmission) = − . ± . (at σ). using our model's dependence of the infection rate constant on mobility, this would correspond to an equivalent social mobility reduction of ∆m mask − % ± %. warmer, more humid weather has also considered a factor that could slow the epidemic (e.g., wang et al., a; notari, ; xu et al., a). annual changes in specific humidity are ∆h g/kg ( figure b in supplementary material), which can be translated in our model to an effective mobility decrease of ∆m summer − % ± %. combining these two effects could, in this simple analysis, yield a modestly effective defense for the summer months: ∆m mask+summer − % ± %. therefore, this could be a reasonable strategy for most communities to manage the covid- epidemic at the aforementioned - % level of mobility needed to arrive at herd immunity with the least excess death. more stringent measures would be required to keep mortality below that level. of course, this general prescription would need to be fine-tuned for the specific conditions of each community. by simultaneously considering the time series of mortality incidence in every us county, and controlling for the time-varying effects of local social distancing interventions, we demonstrated for the first time a dependence of the epidemic growth of covid- on population density, as well as other climate, demographic, and population factors. we further constructed a realistic, but simple, first-principles model of infection transmission that allowed us to extend our heuristic linear model of the dataset into a predictive nonlinear model, which provided a better fit to the data (with the same number of parameters), and which also accurately predicted latetime data after training on only an earlier portion of the data set. this suggests that the model is well-calibrated to predict future incidence of covid- , given realistic predictions/assumptions of future intervention and climate factors. we summarized some of these predictions in the final section of results, notably that only a small fraction of us counties (with less than ten percent of the population) seem to have reached the level of herd immunity, and that relaxation of mobility restrictions without counter-measures (e.g., universal mask usage) will likely lead to increased daily mortality rates, beyond that seen in the spring of . in any epidemiological model, the infection rate of a disease is assumed proportional to population density (jong, diekmann, and heesterbeek, ) , but, to our knowledge, its explicit effect in a real-world respiratory virus epidemic has not been demonstrated. the universal reach of the covid- pandemic, and the diversity of communities affected have provided an opportunity to verify this dependence. indeed, as we show here, it must be accounted for to see the effects of weaker drivers, such as weather and demographics. a recent study of covid- in the united states, working with a similar dataset, saw no significant effect due to pop- ulation density (hamidi, sabouri, and ewing, ), but our analysis differs in a number of important ways. first, we have taken a dynamic approach, evaluating the time-dependence of the growth rate of mortality incidence, rather than a single static measure for each county, which allowed us to account for the changing effects of weather, mobility, and the density of susceptible individuals. second, we have included an explicit and real-time measurement of social mobility, i.e., cell phone mobility data provided by google (fitzpatrick and karen, ), allowing us to control for the dominant effect of intervention. finally, and perhaps most importantly, we calculate for each county an estimate of the "lived" population density, called the population-weighted population density (pwd) (craig, ) , which is more meaningful than the standard population per political area. as with any population-scale measure, this serves as a proxy -here, for estimating the average rate of encounters between infectious and susceptible people -but we believe that pwd is a better proxy than standard population density, and it is becoming more prevalent, e.g., in census work (dorling and atkins, ; wilson, ) . we also found a significant dependence of the mortality growth rate on specific humidity (although since temperature and humidity were highly correlated, a replacement with temperature was approximately equivalent), indicating that the disease spread more rapidly in drier (cooler) regions. there is a large body of research on the effects of temperature and humidity on the transmission of other respiratory viruses (moriyama, hugentobler, and iwasaki, ; kudo et al., ) , specifically influenza (barreca and shimshack, ). influenza was found to transmit more efficiently between guinea pigs in low relative-humidity and temperature conditions (lowen et al., ) , although re-analysis of this work pointed to absolute humidity (e.g., specific humidity) as the ultimate controller of transmission (shaman and kohn, ) . although the mechanistic origin of humidity's role has not been completely clarified, theory and experiments have suggested a snowballing effect on small respiratory droplets that cause them to drop more quickly in high-humidity conditions (tellier, ; noti et al., ; marr et al., ) , along with a role for evaporation and the environmental stability of virus particles (morawska, ; marr et al., ) . it has also been shown that the onset of the influenza season (shaman et al., ; shaman, goldstein, and lipsitch, ) -which generally occurs between late-fall and early-spring, but is usually quite sharply peaked for a given strain (h n , h n , or influenza b) -and its mortality (barreca and shimshack, ) are linked to drops in absolute humidity. it is thought that humidity or temperature could be the annual periodic driver in the resonance effect causing these acute seasonal outbreaks of influenza (dushoff et al., ; tamerius et al., ) , although other influences, such as school diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states (moriyama, hugentobler, and iwasaki, ; neher et al., ) , and there have been some preliminary reports of a dependence on weather factors (xu et al., b; schell et al., ) . we believe that our results represent the most definitive evidence yet for the role of weather, but emphasize that it is a weak, secondary driver, especially in the early stages of this pandemic where the susceptible fraction of the population remains large (baker et al., ) . indeed, the current early-summer rebound of covid- in the relatively dry and hot regions of the southwest suggests that the disease spread will not soon be controlled by seasonality. we developed a new model of infection in the framework of a renewal equation (see, e.g., champredon, dushoff, and earn, and references therein), which we could formally solve for the exponential growth rate. the incubation period in the model was determined by a random walk through the stages of infection, yielding a non-exponential distribution of the generation interval, thus imposing more realistic delays to infectiousness than, e.g., the standard seir model. in this formulation, we did not make the standard compartmental model assumption that the infection of an individual induces an autonomous, sequential passage from exposure, to infectiousness, to recovery or death; indeed, the model does not explicitly account for recovered or dead individuals. this freedom allows for, e.g., a back passage from infectious to noninfectious (via the underlying random walk) and a variable rate of recovery or death. we assumed only that the exponential growth in mortality incidence matched (with delay) that of the infected incidence -the primary dynamical quantity in the renewal approachand we let the cumulative dead count predict susceptible density -the second dynamical variable in the renewal approach -under the assumption that deaths arise from a distinct subset of the population, with lower mobility behavior than those that drive infection (see supplementary material) . therefore, we fitted the model to the (rolling two-week estimates of the) covid- mortality incidence growth rate values, λ , for all counties and all times, and used the per capita mortality averaged over that period, f d , to determine susceptible density. regression to this nonlinear model was much improved over linear regression, and, once calibrated on an early portion of the county mortality incidence time series, the model accurately predicted the remaining incidence. because we accounted for the precise effects of social mobility in fitting our model to the actual epidemic growth and decline, we were then able to, on a county-bycounty basis, "turn off" mobility restrictions and estimate the level of cumulative mortality at which sars-cov- would fail to spread even without social distancing measures, i.e., we estimated the threshold for "herd immunity." meeting this threshold prior to the distribution of a vaccine should not be a goal of any community, because it implies substantial mortality, but the threshold is a useful benchmark to evaluate the potential for local outbreaks following the first wave of covid- in spring . we found that a few counties in the united states have indeed reached herd immunity in this estimation -i.e., their predicted mortality growth rate, assuming baseline mobility, was negative -including counties in the immediate vicinity of new york city, detroit, new orleans, and albany, georgia. a number of other counties were found to be at or close to the threshold, including much of the greater new york city and boston areas, and the four corners, navajo nation, region in the southwest. all other regions were found to be far from the threshold for herd immunity, and therefore are susceptible to ongoing or restarted outbreaks. these determinations should be taken with caution, however. in this analysis, we estimated that the remaining fraction of susceptible individuals in the counties at or near the herd immunity threshold was in the range of . % to % (see supplementary materials) . this is in strong tension with initial seroprevalence studies (rosenberg et al., ; havers et al., a) which placed the fraction of immune individuals in new york city at % in late march and % in late april, implying that perhaps % of that population remains susceptible today. we hypothesize that the pool of susceptible individuals driving the epidemic in our model is a subset of the total population -likely those with the highest mobility and geographic reachwhile a different subset, with very low baseline mobility, contributes most of the mortality (see supplementary ma-diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states terial). thus, the near total depletion of the susceptible pool we see associated with herd immunity corresponds to the highly-mobile subset, while the low-mobility subset could remain largely susceptible. one could explicitly consider such factors of population heterogeneity in a model -e.g., implementing a saturation of infectivity as a proxy for a clustering effect (capasso and serio, ; mollison, ; de boer, ; farrell et al., )but we found (in results not shown) that the introduction of additional of parameters left portions of the model unidentifiable. despite these cautions, it is interesting to note that the epidemic curves (mortality incidence over time) for those counties that we have predicted an approach to herd immunity are qualitatively different than those we have not. specifically, the exponential rise in these counties is followed by a peak and a sharp decline -rather than the flattening seen in most regions -which is a typical feature of epidemic resolution by susceptible depletion. at the time of this writing, in early summer , confirmed cases are again rising sharply in many locations across the united states -particularly in areas of the south and west that were spared significant mortality in the spring wave. the horizon for an effective and fully-deployed vaccine still appears to be at least a year away. initial studies of neutralizing antibodies in recovered covid- patients, however, suggest a waning immune response after only - months, with % of those that were asymptomatic becoming seronegative in that time period (long et al., ) . although the antiviral remdesivir (beigel et al., ; grein et al., ; wang et al., b) and the steroid dexamethasone (horby et al., ) have shown some promise in treating covid- patients, the action of remdesivir is quite weak, and high-dose steroids can only be utilized for the most critical cases. therefore, the management of this pandemic will likely require non-pharmaceutical intervention -including universal social distancing and mask-wearing, along with targeted closures of businesses and community gathering places -for years in the future. the analysis and prescriptive guidance we have presented here should help to target these approaches to local communities, based on their particular demographic, geographic, and climate characteristics, and can be facilitated through our online simulator dashboard. finally, although we have focused our analysis on the united states, due to the convenience of a diverse and voluminous data set, the method and results should be applicable to any community worldwide, and we intend to extend our analysis in forthcoming work. baker, rachel e et al. ( ) . "susceptible supply limits the role of climate in the early sars-cov- pandemic". in: science. barreca, alan i. and jay p. shimshack ( ) john d et al. ( ) . "high humidity leads to loss of infectious influenza virus from simulated coughs". in: plos one . , e . oliveiros, barbara et al. ( ) . "role of temperature and humidity in the modulation of the doubling time of covid- cases". in: medrxiv. park, sang woo et al. ( ) . "reconciling earlyoutbreak estimates of the basic reproductive number and its uncertainty: framework and applications to the novel coronavirus (sars-cov- ) outbreak". in: medrxiv. pearce, n et al. ( ) . "accurate statistics on are essential for policy guidance and decisions." in: american journal of public health, e . roberts, mg and jap heesterbeek ( ) . "modelconsistent estimation of the basic reproduction number from the incidence of an emerging infection". in: journal of mathematical biology . (figure was obtained from the noao global surface summary of the day (gsod) database (national oceanic and atmospheric observatory, ). the nearest wban station with daily dew point and pressure values (for calculation of specific humidity), and daily average temperature was chosen for each county or metropolitan region. weather data was averaged over a two-week period for λ , and over a window equal to the growth period for metropolitan regions. google's covid- community mobility reports dataset (fitzpatrick and karen, ), specifically "workplace mobility," was used to estimate the human social mobility in each county ( figure ). population-weighted population density (or, population weighted density, pwd) (craig, ; wilson, ; dorling and atkins, ) , was calculated using the global human settlement population raster dataset (european commission joint research centre, ), which contains m-resolution population values worldwide, taken from census data. the value of pwd for a countyor for a set of counties, in the metropolitan region analysis -was calculated as the population-weighted average of density over all ( m) -area pixels contained within the region, i.e., where p j is the value (i.e., the population) of the jth pixel, a j = . km is the area of each pixel (the ghs-pop image uses the equal-area molleweide projection), and i p i is the total population of the region. this measure has also been called the lived population density because it is the population density experienced by the average person. in high density counties, the population weighted density pwd is close to the mean density of the county d = pop/area, suggesting a uniform distribution of population (see figure ). however, in lower density counties, the mean density is much lower than the population weighted density, due to heterogeneous dense pockets of population amidst vast empty spaces outlined diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states by political boundaries. to represent the degree to which the population density changes across the region (county or metropolitan region) we define the population sparsity index, γ. assuming that the population-weighted population density declines approximately as a power law with "pixel" area, pwd √ area ∼ area −γ , we define: in other words we estimate the assumed power-law decline using two data points. the distribution of γ and its correlation with county population and population density are shown in figure ( ) . we can see that γ ranges from . (i.e., very uniform) for the most populous/dense counties to . (i.e. very sparse) for least populated/dense counties. for reference, the value of γ for new york city is . . for each of the top metropolitan regions (united states census, b), a logarithmic-scale population heat map, windowed from the full ghs-pop raster image, was used to select a minimal connected set of us counties enclosing the region of population enhancement. in this process, overlap and merger reduced the total number of metropolitan regions under consideration to . as is discussed in the main text, nearly every metropolitan region saw, in mid-march , an exponential increase of daily confirmed cases, followed by a flat/plateau period of nearly constant daily confirmed cases. in a few cases, the second phase -primarily caused by the country-wide lockdown -lasted only days or weeks (possibly signaling a depletion of the susceptible population, see discussion in main text), but for most metropolitan regions the plateau persisted for months (indeed, persists or is again increasing at the time of this writing). thus, the initial value of the exponential growth rate, λ, of daily confirmed cases could be reliably and automatically estimated by fitting the case numbers to a logistic function where t represents the transition time from exponential growth to a constant, f max is the plateau value in case numbers, and f logistic (t) ∝ exp[λt] for t t . fits were performed on the logarithm of the case numbers, yielding the maximum likelihood estimation of parameters under the assumption lognormally-distributed errors (an analysis of the fit residuals, not shown, confirmed this assumption: case number fluctuations exhibit a variance far in excess of poisson noise, but are well modeled by a log-normal probability density function with constant width), and associated estimates of the variance in each parameter. to avoid polluting the exponential growth phase with singular early cases, a "detection limit" of was imposed, and all daily case values less than or equal to that limit were ignored in fitting. the only manual intervention required for this fit was the specification of the upper limit of its range, i.e., the end of the plateau region, for each data set. to analyze the effect of demographic, population, mobility, and weather variables on this initial growth rate, we perform a weighted linear regression to the lambda values (and their standard errors) of the metropolitan regions. to choose representative cities for the visual examples in figures a and c , we performed an additional logistic fit to the mortality incidence data of each region and retained for figure c only those that had ( ) less than % error in both growth rates, and ( ) |λ case − λ death | < . d − . this was done in an effort to specifically comment on or highlight only those cities for which the growth rate was accurately determined, and was well correlated with the more reliable measure, mortality growth, that we used for the remainder of the analysis. a standard weighted least squares analysis was performed on the measured exponential growth rate, λ , as a function of demographic, mobility, population and weather variables, with weights equal to inverse root of the estimated variance. we construct a model where, in the standard analogy to chemical reaction kinetics, the incidence of infections per unit area at time, i(t), is proportional to the product of the density of susceptible individuals, s(t), and the density of infected individuals, i(t). but, we allow for the rate constant for infection in the encounter, β, to depend on the infected individual's "stage" of infection, c, with c = immediately following infection. the incidence then has the form: where i(c, t) is the density of infected per stage at time t, and the first equality expresses that we neglect changes in a physical picture of collisions, the rate constant of infection is β(c) = σv eff (c), i.e., the scattering cross section of an encounter between a susceptible individual and an infectious individual in stage c, σ, multiplied by their relative velocity, v. to the susceptible population by all means other than infection. the density of infected individuals is found by integration over the stages of infection, if the rate constant were taken to be independent of stage, i.e., β(c) =β, we would obtain the familiar expressioṅ s(t) = −βs(t)i(t). we will assume spatial homogeneity and that the total density of individuals is constant and equal to s( ) for a particular region, but, that the density could vary when comparing different regions. we assume that an infected individual's evolution through the stages of infection, c, follows a gaussian random walk in time, but modulated by an exponential rate, d, of death or recovery. therefore we have where a is the "age" of an infection (time since infection), and the probability density function for the stage at a given age is given by where τ is the characteristic time scale of the random walk . integrating the expression for i(c, t) over all stages and taking the derivative with respect to time yields the familiar expressionİ(t) = i(t) − di(t), showing that the model reduces to the sir model if a stageindependent rate constant,β, is assumed. as we show here, using the random walk to specify the dependence of infection stage on time allows for both a non-exponential distribution of delays to infectiousness (which is more realistic than that of the simplest model with incubation, the seir model) and a formal solution for the exponential growth rate. inserting the expression for i(t, c) into the incidence equation yields which is in the form of a renewal equation (heesterbeek and dietz, ; champredon and dushoff, ; champredon, dushoff, and earn, ) , with the bracketed expression being the expected infectivity of an individual with infection age a. to obtain the simplest nontrivial incubation period, we assume that β(c) =β Θ(c − )where Θ(x) is the heaviside step function -meaning diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states that an infected individual is only infectious once they reach stage c = , and the infection rate constant is otherwise unchanging. this implies that the incidence is where is the probability that an individual infected a time units ago is infectious. if we now assume that the density of susceptibles is constant s(t) =s over some interval of time, and that the incidence grows (or decays) exponentially in that interval, i(t) = ae λt , we find which, assuming λ + d > (i.e., the exponential growth rate cannot go below −d), can be integrated to obtain this expression for (λ + d) has a formal solution in terms of the lambert w-function, with simple asymptotic forms: for the early stages of the epidemic, when we can assume that the population of susceptibles is approximately constant and large, we see that the growth rate depends approximately linearly on the square of the logarithm of the density. in later stages, when either the base contact rate declines due to social distancing interventions, or the population of susceptibles decreases, we see that the exponential rate takes the value λ ≈ −d. in practice, we utilize the exact lambert w-function expression as our "nonlinear model" for fitting λ , where we parameterize β and τ by the demographic, population, and weather variables (see main text). to estimate the susceptible density,s, in this procedure we must use the reported mortality statistics. thus far we have not specified the dynamics of death. we now make the assumption that the probability of death increases proportionally to the number of exposures an individual experiences. as we prove in a separate section, below, this implies that the susceptible density is related to the fraction of dead in the community, f d = d tot /n (where d tot is the cumulative mortality and n is the total population), by the basic reproduction number, r , and the distribution of generation intervals, g(t g ), are defined (champredon and dushoff, ; nishiura, ) through the function f(a): ( ) the generation interval (or, generation time), t g , is the time between infections of an infector-infectee pair, and is often estimated from clinical data by the serial interval, which is the time between the start of symptoms (britton and scalia tomba, ), and the basic reproduction number is the average number of infectees produced by a single infected individual, assuming a completely susceptible population. these quantities can be calculated exactly for our model, as and where the expected value and variance of the generation interval are then: relation between the remaining susceptible density, s(t) and the death fraction, f d (t) in epidemic models the infection of susceptible individuals is typically determined bẏ where i * is the density of infectious (contagious) individuals, and for our model, βsi * is the right-hand side of eqn. . this can be solved, formally, as: alternatively, the susceptible density can be expressed in terms of the cumulative number of infected individuals, i tot , i.e., diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states where f i (t) = i tot /n , with n the total population. when fitting the exponential growth rate of mortality, λ (t) to our nonlinear model, eqn. ( ) (see main text), we must estimate the value of the susceptible density driving growth at that time. without any reliable information about the true infected or infectious populations, we must do so using the mortality statistics. we show here how the previous two equations can be used, along with reasonable assumptions about distinct sub-populations driving infection and death, to determine a relationship between the reported cumulative mortality (per capita) and the remaining susceptible density. our basic assumption is that there are two different categories of susceptible individuals underlying the dynamics of the epidemic: (a) highly mobile individuals with a large geographic reach that frequently interact with other individuals (in particular, infectious individuals) and thus drive the dynamics of infection (these could be termed "super-spreaders" (liu, eggo, and kucharski, ) ); and (b) essentially non-mobile individuals that have quite rare contacts with infectious individuals, but have a much higher probability of death once infected, and therefore make up the majority of the mortality burden. the dynamics of each susceptible population is governed by an equation of the form in eqn. ( ), with a common density of infectious individuals, i * , but with different rate constants, β a β b . from eqn. ( ), we see that the susceptible densities of the two populations are then related, at any time, by: expressing the non-mobile population in terms of the cumulative fraction infected, we have and, assuming that the infection fatality rate (ifr) is a constant factor, f d (t) = ifr × f i (t − ∆t), where ∆t is the delay from infection to death, we can write: finally, having assumed that the ratio of infection rates is large, we can approximate this as: the "a" category of individuals, as defined above, are exactly those individuals driving the infection in our model (and, presumably, in the real world), and, therefore, the susceptible density s a is exactly that which must be estimated for eqn. ( ). on the other side, with people aged and over accounting for ∼ % of covid- deaths, and with approximately ∼ % of deaths linked to nursing homes, the mortality statistics are clearly tracing individuals similar to category "b." therefore, we use this relationship, to estimate the susceptible density in terms of the reported per capita mortality, where we assume s( ) is proportional to the population weighted density (pwd). we also considered the standard approach, in which the population is a single homogeneous group. in that case, the susceptible density could be estimated as ( ) in testing both models, we found that the two-component population scenario was preferred by the data at the ∼ σ confidence level, with the homogeneous population model failing to capture the observed dependence of the growth rate on the per capita mortality (figure ). the broader implications of our assumption of two populations is that the required proportion of individuals with immunity for "herd immunity" to take effect, is lower than population with homogeneous mobility characteristics, i.e., the epidemic will slow as a significant proportion of the "super-spreader" category have been infected (category a, above), regardless of the level of infection and immunity in the rest of the population. indeed, the effect of population heterogeneity on lowering the "herd immunity" threshold for covid- was recently noted (britton, ball, and trapman, ), and will be important in interpreting the results of randomized serology tests across the entire population (havers et al., b) . the nonlinear epidemic model described above posits that the incubation of sars-cov virus within an infected individual can be modelled by a stochastic random walk starting at zero, with excursions beyond ± corresponding to episode(s) of infectiousness. this makes our model distinct from the standard se m i n r compartmental models (see, e.g., (champredon, dushoff, and earn, ) ), where the progress of the disease is only in one direction -e → e → . . . → i → i → . . . -while in our model (figure ) , the individual can jump back and forth between different stages (with the obvious exception of death), with a constant exit rate of d for quarantine, recovery, or death. this can be described using a (leaky) diffusion equation: based on this picture, and the best-fit parameters to the us county mortality data (table ) , we can infer the probabilities associated with the different stages of the disease. for example, by looking at the steady-state solutions of equation ( ), we can compute the probability that an exposed individual (who starts at c = ) will ever become infectious (i.e., make it beyond c = c inf = ): this is plotted as a function of the median age of the community in figure ( a) . for example, for the median age of all us counties, a = . -yr, we get: p inf ( . years) = . + . − . ( % c.l.), i.e., less than % of exposed individuals will ever be able to infect others, although this fraction increases in older communities. next, we can compute the distribution of times for the onset of infectiousness, i.e., the incubation period. this can be done by using a first crossing probability of a random walk, which we did by solving equation diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states ( ) using a discrete fourier series in the ( , + ) interval. the resulting probability density is shown in figure ( b), again showing a shorter incubation period in older communities. finally, we can compute the probability density function for the generation interval, g(t g ), defined in equation ( ) (figure c ). this shows a similar qualitative dependence on age as the incubation period, but the median incubation period is, as expected, shorter than the generation interval for each age group. using eqn. ( ) and our parameterization of τ , we find a mean generation interval of e[t g ]( . years) = ± d . this estimate is much longer than those found by tracking the serial interval (time from between the start of symptoms for an infector-infectee pair) in covid- patients (ganyani et al., ; nishiura, linton, and akhmetzhanov, ) , which are on the order of - d. it is possible that the long tail of these distributions, generated by the slow asymptotic exponential decay at rate d ≈ . d − , raises the mean generation interval, while a clinical study, is necessarily biased toward shorter serial intervals. one of the most pressing questions in any exercise in physical modelling is whether we have a good understanding of the uncertainty in the predictions of the model. while we have an estimate of the measurement uncertainties for the mortality growth rates, λ , which we discussed in the main text, we also should characterize whether the deviation of the best-fit model from the measurements are consistent with statistical errors. to evaluate this, we can look at the average of the ratio of the variance of the model residuals to that of the measurement errors, otherwise known as reduced χ , or χ red . this is shown in figure ( ) , demonstrating that we see no systematic error in model that is significantly bigger than statistical errors, across counties with different populations. as another consistency check, table ( ) examines whether the parameters of the model change significantly from urban counties with large, uniform populations, to rural counties with a small and more sparse population (figures - ). from counties with enough covid mortality data, roughly those with population inhabit half of the total population, which we chose as our threshold, separating large from small counties. we notice no statistically significant difference, and table ( ) even suggests that fisher errors quoted here might be overestimating the true errors. this comparison brings further confidence in the universality of the nonlinear model across geography and demography. on average, we find that (either county-weighted or population-weighted) χ diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of table ( ), we use temperature rather than specific humidity (ct rather than ch), as the latter was not available for some small counties. nevertheless, the parameters remain also statistically consistent with table ( ). local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states heesterbeek first case of novel coronavirus in the united states effect of dexamethasone in hospitalized patients with covid- : preliminary report". in: medrxiv herd immunity and herd effect: new insights and definitions covid- data repository by the center for systems science and engineering (csse) at johns hopkins university how does transmission of infection depend on population size? early dynamics of transmission and control of covid- : a mathematical modelling study low ambient humidity impairs barrier function and innate resistance against influenza infection defining the pandemic at the state level: sequence-based epidemiology of the sars-cov- virus by the arizona covid- genomics union (acgu) covid- : a need for real-time monitoring of weekly excess deaths early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical and immunological assessment of asymptomatic sars-cov- infections influenza virus transmission is dependent on relative humidity and temperature mechanistic insights into the effect of humidity on airborne influenza virus survival, transmission and incidence how deadly is covid- ? a rigorous analysis of excess mortality and agedependent fatality rates in italy sensitivity analysis of simple endemic models droplet fate in indoor environments, or can we prevent the spread of infection? seasonality of respiratory viral infections global surface summary of the day (gsod). ftp.ncdc. noaa.gov potential impact of seasonal forcing on a sars-cov- pandemic time variations in the generation time of an infectious disease: implications for sampling to appropriately quantify transmission potential serial interval of novel coronavirus (covid- ) infections". in: international journal of infectious diseases temperature dependence of covid- transmission we are indebted to helpful comments and discussions by our colleagues, in particular bruce bassett, ghazal geshnizjani, david spergel, and lee smolin. na is partially supported by perimeter institute for theoretical physics. research at perimeter institute is supported in part by the government of canada through the department of innovation, science and economic development canada and by the province of ontario through the ministry of colleges and universities. red . , suggesting that the model errors are only % bigger than statistical errors.we further compare the model-prediction vs measured mortality growth rate in figure ( ) for all our available data. we find that the -σ error in the model prediction (in excess measurement errors) is on average ±σ = ± . , i.e. . % error in the daily mortality growth rate. this is shown in figure ( ) as the red region, which compares the model prediction with the observed mortality growth rates. we can also see that there appears to be no significant systematic deviation from the predictions, at least for λ < . /day.given an understanding of the physical model and its uncertainties, we can provide realistic simulations to forecast the future of mortality in any community, similar to those provided in the main text (figure ) , which can be made on-demand using our online dashboard: https://wolfr.am/covid dash.in order to perform these simulations, we follow these simple steps. to predict the daily mortality on day t + , d(t + ), we use the prior days of d(t), as well as the total mortality up to that point: ( ), plugging in prior total mortality, county information, weather, mobility and parameters in table to find λ . every simulation uses a random realization of model parameters (from their posterior fits), which remain fixed through that simulation. . add the random model uncertainty to λ using: where g t s are random independent numbers drawn from a unit-variance normal distribution. this captures the model uncertainty mentioned above, while ensuring that it remains correlated across the days that are used to define λ . . having fixed the logarithmic slope for daily mortality λ , find the best-fit intercept and its standard error for ln[d(t ) + / ] for the preceding days, i.e. t − ≤ t ≤ t, which can then be used to find a random realization for ln[d(t + ) + / ] . advance to next day and return to step . key: cord- -sxl g p authors: mathews, fiona title: chapter zoonoses in wildlife: integrating ecology into management date: - - journal: adv parasitol doi: . /s - x( ) - sha: doc_id: cord_uid: sxl g p zoonoses in wildlife not only play an important ecological role, but pose significant threats to the health of humans, domestic animals and some endangered species. more than two‐thirds of emerging, or re‐emerging, infectious diseases are thought to originate in wildlife. despite this, co‐ordinated surveillance schemes are rare, and most efforts at disease control operate at the level of crisis management. this review examines the pathways linking zoonoses in wildlife with infection in other hosts, using examples from a range of key zoonoses, including european bat lyssaviruses and bovine tuberculosis. ecologically based control, including the management of conditions leading to spill‐overs into target host populations, is likely to be more effective and sustainable than simple reductions in wildlife populations alone. bovine tuberculosis. ecologically based control, including the management of conditions leading to spill-overs into target host populations, is likely to be more effective and sustainable than simple reductions in wildlife populations alone. parasites and pathogens in wildlife are a natural part of biodiversity. an abundance of theoretical studies indicate that they have key roles in ecological and processes, including the regulation of population size may and anderson, ) and the maintenance of genetic diversity (may and anderson, ; read et al., ) . occasional field experiments have also demonstrated impacts of sublethal infections on reproductive rates (munger and karasov, ) and susceptibility of wildlife to predation (hudson et al., ) . yet the vast majority of empirical studies consider wildlife pathogens and parasites only if they threaten the health of humans or their domestic animals, and often overlook their natural history. partly this reflects the priorities of funding agencies; and their concerns are not trivial. more than % of emerging (or re-emerging) pathogens of humans are thought to have wild animals as their natural reservoirs (taylor et al., ) . examples include sars-cov (severe acute respiratory syndrome coronavirus), avian influenza a (h n ) virus (bird flu), nipah virus, hantavirus and west nile virus. the economic imperative for controlling zoonoses that affect domestic stock can be very strong. for example, bovine tuberculosis (btb) in the united kingdom undoubtedly has a reservoir in wild badger populations, and the direct cost of the disease to agriculture is projected to reach £ billion by (department for environment, food and rural affairs (defra), ). it has been recognised relatively recently that disease can also pose a serious threat to the survival of endangered wildlife (lyles and dobson, ; may, ; smith, ) . this can either be through direct mortality, where losses are greater than the birth rate, or through effects on birth rate, longevity and survival, which suppress the population size to a level that renders it susceptible to extinction by stochastic effects (table . ). generalist pathogens with a wide host range are particularly problematic, since even virulent species can persist in alternative hosts while driving the rare host to extinction (begon and bowers, ) . although remaining low on the list of priorities compared with other threats such as habitat loss, efforts are therefore sometimes now made to control infectious diseases for conservation reasons. examples of recent successes include the control of canine distemper virus in black-footed ferrets (mustela nigripes) (williams et al., ) , and rabies in african wild dogs (lycaon pictus) (hofmayer et al., ) and ethiopian wolves (canis simensis) (haydon et al., ) . in europe alone, there are at least zoonotic parasites and pathogens in wildlife that are known to be important either to public health or the agricultural economy (artois et al., ) . for many other infectious agents, such as cryptosporidium parvum, the epidemiological role of wildlife is unknown. despite the many attempts to control zoonoses in wildlife, the success rate is poor. typically, measures are adopted as crisis management (usually in the form of culling) following an outbreak, with little understanding of the ecology of species or its relationship to the pathogen. crisis management also means that proper scientific designs with appropriate controls are often lacking; it is therefore difficult to evaluate the effectiveness of a given intervention. even where there is a long history of attempts to control a disease through the management of a wildlife reservoir, the results have not been encouraging. for example, efforts over the last years to control btb in cattle in the united kingdom by culling of badgers has failed to yield significant benefits, with analyses of the recent randomised controlled trial of badger culling concluding that culling could not contribute meaningfully to future control strategies for btb (donnelly et al., ) . similarly, the culling of foxes has been discounted as a means of rabies control in western europe (blancou et al., ) . however, success has been achieved through the use of widespread vaccination (administered via bait) (aubert, ) . rabies is currently the only example of a widespread strategy of vaccination being favoured over the control of the host species (artois et al., ) . this review considers the ecology of zoonoses in wildlife and the links between infection in wildlife and humans or livestock. it proposes that a shift to ecologically based control, explicitly considering the natural history of wildlife hosts and their pathogens, is crucial in minimising the risk presented to humans, domestic animals and endangered species from zoonoses. this approach will also yield benefits for the conservation and welfare status of wild animals. notwithstanding the complexities of specific relationships, the probability of a zoonosis being passed from wildlife into another host population, be it humans, domestic stock or an endangered wild species, is always influenced by several key parameters. these are the intensity of infection in the reservoir hosts; the size, or depending on the case, the density, of the infected host population; the degree and nature of the contact between infected individuals (or infectious particles in the environment such as infected faeces); and the susceptibility of the in-contact animal. (for indirectly transmitted parasites and pathogens, the role of vectors and/or intermediate hosts must also be considered.) whether the zoonosis persists after initial invasion is also determined by the new host's population size. a great variety of models has been developed to describe the transmission dynamics of macro-and microparasites, taking into account the nuances of particular host and parasite population structures (diekmann and heesterbeek, ; heesterbeek and roberts, ; scott, ; scott and smith, ). yet empirical research has lagged behind the theoretical advances. the legacy of researchers like elton and chitty (chitty, (chitty, , elton, ; elton et al., elton et al., , , who sought not only to describe pathogens but to understand their ecological role, has not been sustained. (there are a few notable exceptions, including the long-term studies of small mammals in the north of england (beldomenico et al., a,b; feore et al., ) ; rodent reservoirs of hantavirus in the united states (calisher et al., ; mills et al., ) and macroparasite infections in laboratory models (ehman and scott, ; scott, ; scott and anderson, ; scott and smith, ) .) this deficiency was noted in a key text in the field in (grenfell and dobson, ) and again in the follow-up publication in (hudson et al., ) . we lack even species lists of parasites and pathogens for most, if not all, wild animals. while pathogens that affect international trade are reported to the world organization for animal health (oie), and many of these affect wildlife (see artois et al., ) for the lengthy list of those likely to affect wildlife in europe), there is no agreed systematic programme of surveillance (kulken et al., ) . even where programmes exist, they lack integration with surveillance in humans and domestic animals at both local and international scales. disease surveillance in wildlife is usually driven by outbreaks in humans or domestic animals (childs, ) . virulent pathogens are, therefore, more likely to be detected than more benign ones (williamson et al., ) . such studies are also, by their nature, not designed to screen for a range of pathogens, so opportunities to investigate the epidemiology and ecology of coinfections are often lost. systematic surveillance of representative samples of the population is difficult and time consuming. yet prevalence estimates can be seriously skewed if the only data available are derived from passive surveillance of carcasses. not only are estimates likely to be too high if they are based on samples of wildlife found dead or sick by the public, but even road kills and game bags are likely to over-represent certain population classes (such as dispersing juvenile male mammals) and animals in compromised health. disease-responsive surveillance also offers little information on the frequency with which transfer events are likely to occur. for example, many of the 'spectacular' epidemics derived from bat viruses, such as hendra virus, nipah virus, sars-cov-like virus, have been observed only a small number of times. we do not know why this should be the case. is transfer of zoonoses from bats to terrestrial vertebrates generally rare due to a lack of appropriate contact? or is there regular inter-specific transmission of other viruses but these go undetected because they lack the extreme pathogenicity of hendra and nipah viruses to stimulate screening efforts? pro-active surveillance of wildlife and of apparently healthy human or livestock populations could help answer these questions. structuring and species specificity of a pathogen in wildlife hosts? screening for european bat lyssaviruses in europe is an exemplary case of research stimulated by public health concerns. the first recorded european bat rabies case was in hamburg in and several other cases were identified subsequently (king et al., ). yet surveillance of bats was not really pursued until a woman in denmark was bitten by a serotine bat (eptesicus serotinus) infected with european bat lyssavirus (eblv ). since then more than rabies-positive bats have been identified across europe; the vast majority being serotine bats infected with eblv- (harris et al., ) . in the united kingdom, screening efforts were intensified following the death of a man in scotland from eblv- in , after apparent contact with many bats in the united kingdom and europe (fooks et al., ) . in contrast with classical rabies (rabv) there is now good evidence that at least some bats (and possibly other animals) can produce neutralising antibodies and survive eblv infection for at least years (serra-cobo et al., ; van der poel et al., ) , and experimental models suggest that eblv- might be inherently less virulent than eblv- (vos et al., ) . eblv- also appears to have a much more restricted geographical range than eblv- , and small numbers of positive bats have been identified in the united kingdom, switzerland, the netherlands, denmark and germany (department for environment, food and rural affairs (defra), ; racey et al., ; vos, ; vos et al., ) . these cases have all been in the closely related daubenton's (myotis daubentoni) and pond bats (m. dasycneme). structuring of eblvs therefore is apparent from these data both across geographical areas and across species. the serotine bat occurs over most of europe, extending north to latitude (england south of the wash estuary, denmark and southern sweden); daubenton's bats are common across europe; and the pond bat is present in a wide band across central and eastern europe (between and latitude; absent from the united kingdom (schober and grimmberger, ) ). yet neither eblv- nor eblv- appears throughout their hosts' ranges. some suggest that in the case of eblv- , this may be because long-distance travel is uncommon in serotines, the primary host (vos et al., ) . yet the species is widely distributed, and it is unlikely that there are gaps between populations that could not be travelled with relative ease; dispersing movements of up to km have also been recorded (hutterer et al., ) . interestingly, eblv- also appears to have a patchy distribution, despite its host species, at least in continental europe, being migratory over long distances (vos, ) . whether the geographical distribution is, in reality, less patchy than it currently appears requires co-ordinated surveillance effort and a willingness by statutory authorities to publish test results even if they are negative. it is clear that active surveillance (systematic screening of bats in the wild) has been undertaken in a few countries only, and passive surveillance (submission of dead bats by members of the public for screening) has involved few, if any, animals in a number of european countries, including portugal, ireland, greece, the czech republic and slovakia (racey et al., ) . a range of european bats, most of which are common and widespread, has been identified as having active eblv infections in addition to the key hosts (table . ). it is striking then that the vast majority of reported cases come from just three species. undoubtedly, the numbers of bats of each species submitted by the public does not match their abundance in the wild, but is influenced by the closeness of their contact with humans (and their cats, which are a major cause of bat mortality). for example, few woodland specialists have been submitted, whereas bats that frequently roost in houses, particularly pipistrelles, long-eared bats and possibly serotines, are over-represented (harris et al., ) . even active surveillance does not attempt comprehensive surveys of all species in proportion to their abundance: instead, it focuses on the three species already identified as being important sources of eblvs, potentially failing to estimate properly the prevalence in others. despite these limitations, the data clearly suggest that species partitioning occurs. the common pipistrelle bat is known to be susceptible to experimental infection with eblv- (kuzmin and botvinkin, ) . yet none of the more than , pipistrelles (p. pipistrellus and also p. pygmaeus, which is cryptic with p. pipistrellus) surveyed in the netherlands, france and the united kingdom (harris et al., ; picard-meyer et al., ; van der poel et al., ) has proved positive for the virus. whether structuring across bat species driven by differing immunoresponsiveness to particular eblv types, by a lack of transmission opportunities or by other mechanisms, is unclear. multi-species summer, and particularly hibernation, roosts are known, though the amount of inter-specific direct contact appears to vary by season and species. for example, bats in houses and trees tend to use single-species roosts, even if more than one species is present at the site (park et al., ) . there may be more potential for inter-specific contact at key underground sites used by bats. in a survey of more than , bats of different species roosting in caves in turkey, it was noted that multi-species clusters frequently occurred in the post-hibernation season, but not during hibernation; and the horseshoe bats (rhinolophus spp.) only ever formed single-species clusters (furman and Ö zgü l, ) . many bat species also use swarming sites-enclosed areas often in and around caves-for display purposes. at these sites, hundreds or thousands of bats of mixed species congregate (glover and altringham, ; parsons et al., ) . the amount of contact, for example, via urine or aerosol droplets, between species at these events is unknown. more field research is needed to investigate the opportunities for disease transmission across bat species, and across geographical barriers. interestingly, in the united kingdom, only a single case of exposure to eblv- has been found (the test was able to detect exposure rather than live virus), whereas in other european countries with eblvs, the apparently more pathogenic eblv- is more common (defra, ; racey et al., ; vos, ) . to date, seven daubenton' bats (myotis daubentoni) in the united kingdom have been found to have eblv- infection (defra, ) , the latest case being diagnosed in may . it is notable that although a low prevalence (around %) of seropositivity was detected during active surveillance of daubenton's bats in scotland, live virus was not isolated from any of them (brookes et al., ) . similar results were found in an active-surveillance study in spain, which found that up to % of individuals in some colonies were seropositive for eblv- , but the prevalence of active infection was less than . % (serra-cobo et al., ) . it is currently difficult to interpret these results, but the vertical transmission of antibodies, as well as acquired immunity, is a possibility. while it is clear that eblv- and eblv- can cause deaths in unvaccinated humans, whether natural immune responses and cryptic recovery (i.e., without the virus having invaded the central nervous system and become symptomatic) are possible remains unknown. it is unfortunate that there was been no serological testing of bat workers in the united kingdom to establish the natural prevalence of neutralising antibodies to eblvs prior to . since that date, following the fatality in scotland from eblv- , it has been officially recommended that bat handlers be vaccinated against rabies. the take-up rate of vaccination has been very high. this understandable management of the public-health crisis means that it is now not possible to gather information that would have helped indicate the pathogenicity of eblv- to humans, and also whether exposure was more widespread than the single fatal case. it certainly appears that despite other species being susceptible in experiments, natural spillover into other non-bat hosts to produce clinical symptoms is rare, with the only known case for eblv- being a single stone marten . there are no reports of spill-over for eblv- . the apparently simple task of establishing the prevalence of a pathogen in wild animals can be fraught with difficulty. even assuming that a reasonably random cohort can be sampled, there is usually no opportunity to repeat 'live-tests' in cases of diagnostic uncertainty. establishing values for other key parameters is equally problematic. fundamental data on the sex-and age-distributions of infection are often not recorded. sometimes this is because the surveys (particularly for 'crisis management') were not designed with research in mind. sometimes it is practically difficult for the data to be acquired. bats, for example, can live more than years, yet it is impossible in the absence of long-term banding studies on the particular population being surveyed, to judge the age of animals with much greater accuracy than 'juvenile', 'young of the year', and 'adult'. weight is frequently used as a surrogate for age or maturity, particularly in studies of rodents, but there can be difficulties in distinguishing age from dominance effects, since both are correlated with body mass. the size of the population (or its density) is also often estimated with huge margins of error, as surveyors simply lack the time to undertake detailed ecological studies in addition to collecting clinical samples. distinguishing between different burdens of infection (particularly for macro-parasites) and stages of infection (particularly for micro-parasites) is frequently overlooked. this makes it difficult to use the data to parameterise epidemiological models. for example, animals infected with btb but in which the bacilli are encysted present no risk of transmission at that particular time point, yet these groups are often combined when data from post-mortem examinations are used. the fact that the disease may reactivate at some future time (measured by the overall prevalence) is not relevant to the calculation of the basic reproductive rate of the disease r . by conducting large-scale surveys of representative populations of wildlife on british farms, workers were able to build deterministic models to investigate the likelihood of the disease persisting in each host species. initially they assumed that no between-species transmission was present. using the prevalence of infectious individuals, together with field data on population structure and density derived from the same sites, they computed the basic reproductive number r for each of the species. the analyses showed that even when the maximum likely prevalence was assumed (based on the upper % confidence limit), the r (the basic reproductive rate of the disease) ranged from just . in wood mice to . in rats. (the lower confidence intervals for prevalence always gave r values that were < . ; mathews et al., b .) it is therefore unlikely that the disease would persist within single-host systems in the wild: the animals are unable to pass on the infection to their conspecifics at a rate high enough to maintain the disease. the findings are robust to underdiagnosis of infection: to affect the r materially, the prevalences would need to be have been underestimated very substantially. if, instead of single-host models, we assumed multiple-host systems, then higher prevalences should have been observed in the field than those recorded. alternatively, to achieve the prevalences seen in reality, the withinspecies transmission rate would have to be even lower than the very low value calculated. they have therefore been able to conclude that multi-species transmission of btb within farmland wildlife communities appears unlikely. perhaps the best example of long-term epidemiological studies in wildlife leading to epidemiological models of value to human health comes from studies of hantavirus infection in the united states. large-scale studies of several thousand rodents were conducted by four separate research teams, but were co-ordinated by common methodologies (calisher et al., ; easterbrook et al., b; glass et al., ; mills et al., ) . using longterm datasets, with repeated trapping at set grids, the teams were able to explore key components of the transmission pathway. seropositivity was higher in males and in heavier animals, suggesting horizontal transmission among adult males. decreasing prevalence with age among the youngest deer mice suggests that infected dams confer passive immunity to pups. in the main host of sin nombre virus, the deer mouse (peromyscus maniculatus), gender, age, wounding, season and local relative population densities were linked with the period prevalence of antibody (used as a marker of infection). nevertheless, antibody prevalence and some of the risk factors associated with antibody prevalence, such as relative population density, gender bias and prevalence of wounding, varied significantly among sites and even between nearby trapping arrays at a single site. this suggests that local micro-site-specific differences play an important role in determining relative risk of infection in rodents and, consequently, in humans. these data are now being used in spatially explicit models of the risk of human disease outbreaks (eisen et al., ) . as described for bat lyssaviruses, the contact rates between infectious and susceptible individuals (or a vector and a susceptible) is a critical step in the transmission pathway. yet compared with the effort that goes into improving, for example, the accuracy of a diagnostic test, very little attention is paid to measuring it in the field. this failure may offer some explanation for the difficulties faced in attempted disease control programmes. for example, disease is a primary threat to the survival of the critically endangered ethiopian wolf (canis simensis). since the early s, outbreaks of rabies and canine distemper virus (cdv) have had significant impacts on wolf population dynamics randall et al., randall et al., , . these diseases are maintained in local domestic dog populations, and a programme of dog vaccination was therefore introduced in , with the aim of reducing the population of susceptible dogs and hence the risk of transmission to wolves. attempts were made to achieve coverage of more than % of susceptible dogs during annual vaccination campaigns. this was not an easy task since dogs in ethiopia are used for guarding cattle and are not tame. rabies vaccines have high efficacy, and in theory, this level of coverage should prevent rabies outbreaks % of the time (coleman and dye, ; world health organization, ) . over , vaccinations have taken place, and at least initially, the number of rabies cases in dogs declined (randall et al., ) . nevertheless, a rabies outbreak occurred in wolves in , and could be linked with more than sympatric dogs with clinical symptoms consistent with rabies . mathews has, therefore, been analysing the reasons for the apparent failure of the vaccination strategy, focusing on the population dynamics of the domestic dogs, using data collected by the ethiopian wolf conservation programme. the key factor appears to be the growth of the dog population, which, as in other african countries, is keeping pace with, or even outstripping, human populations (cleaveland et al., ; rhodes et al., ) . eighty-six percent of all households owned dogs, rising to . % in rural areas. virtually nothing is known about the true contact rate between domestic dogs and ethopian wolves. it is clear that interactions do occur as wolf-dog hybrids are seen. we might speculate that diseased dogs, and aggressive dogs that are difficult to vaccinate, might be even more likely to interact with wolves than would healthy ones. some data are available on the demography of the dogs surrounding the bale mountains national park-one of the strongholds of the remaining ethiopian wolf population-as a result of a questionnaire survey administered by the ethiopian wolf conservation programme. the rate of increase in the dog population size appears to be around % per annum, and the turnover rate is also high. this creates a constant influx of new susceptibles into the dog population. it is difficult to keep pace with these, given the financial and logistical constraints on the numbers of visits veterinarians can make to each village. there also appears to be some geographical clustering of vaccination effort, and the implications of pockets of unvaccinated dogs on the probability of rabies transmission to wolves is currently being explored. the vast majority of efforts to control zoonoses in wildlife hosts, rather than in domestic animals, rely on culling strategies. in simple terms, the idea is to depress the population of the reservoir host to a level at which the disease can no longer be sustained, because the density of infected and susceptible hosts is too low. few of these culling programmes have systematically examined either the total population size or the level of population reduction likely to be required to achieve the desired endpoint. even where this has been done, it can be difficult practically, as with vaccination, to achieve the level of coverage desired. the strategy to control btb in badgers and cattle in the united kingdom has had the culling of badgers as its cornerstone for more than years. when it became evident that gradual badger culling was having little or no impact on the incidence of the disease in cattle, a formal review of the programme was introduced, culminating in a large-scale randomised trial of badger culling. this has demonstrated that there is no clear-cut reduction in btb in cattle. on the contrary, whereas the incidence of btb in farms at the centre of km badger culling zones fell by around %, the incidence in farms up to km away from the borders of these zones increased by around % (donnelly, ) . similar results were found in comparable areas where clusters of badgers were removed reactively, following nearby outbreaks of btb in cattle (donnelly et al., ) . at least part of the explanation for the failure to achieve effective btb control is likely to be the alteration in contact rates between infected and susceptible badgers, and also between infected badgers and cattle, as a result of the culling. there has been only one detailed study of m. bovis epizootiology in undisturbed badgers (culling having been suspended at the site, woodchester park in gloucestershire, england in ; delahay et al., ) . this study showed that btb does not spread rapidly at high incidence through badger populations, but rather is distributed patchily among a minority of individuals. social groups are relatively stable, and long-term dispersal movements are uncommon, though shorter movements do occur more regularly (rogers et al., ; vicente et al., ) . there is a correlation between rates of inter-group movement and the incidence of new infections (rogers et al., ; vicente et al., ) . while spatial clusters of infection exist, there is no strong synchrony between neighbouring groups, suggesting that there is only limited transmission between adjacent social groups (delahay et al., ) . both individuals and groups are more likely to be incident cases where the social group was diminishing in size, although there is no apparent relationship with group size itself, suggesting that it is the change in group size, and possibly the associated social dynamics, that influences disease risk (vicente et al., ) . badger culling operations have clear impacts on the behavioural ecology of the survivors. woodroffe et al. ( ) found that badger social group ranges increased among survivors within reactive and pro-active culling areas and along the perimeters of pro-active culling areas. their finding, at a large scale, accords closely with the observations of of individual and group behaviour in two zones of badger removal in england, as well as those of o' corry-crowe et al. ( ) in ireland. in all cases, the spatial organisation of social groups was considerably altered following the culls, with a large increase in the extent of overlaps between social groups (e.g., fig. . ) . the numbers of ranges with which each group overlapped also increased. there was a rather chaotic alteration in population densities (e.g., fig. . ) . in the examples shown, culling was conducted in , largely targeting areas of highest badger density (in effect, the largest social groups). one year later badger density was, unsurprisingly, lower in the culled areas, whereas there had been some increases elsewhere. in , although the population as a whole had not grown, the density remained low, or even fell further, in two removal areas, but increased elsewhere. by and , the distribution of badgers in the study area was radically different from that at the outset, with some previously high density, but culled, areas remaining depauperate . thus, while the population density recovered as a whole, the badgers built up in a different place. this sort of radical redistribution has not been reported in undisturbed populations. the changes have not only implications for absolute contact rates, but also the nature of contacts. for example, bite-wounds-an important route of btb transmission-were more common in the macdonald et al. ( ) study following social perturbation. (post-cull) figure . badger social territories before and after the selective removal of social groups following btb incidents in local farms. social structure also plays an important role in hantavirus transmission. in deer mice, both wounding and sin nombre virus antibody prevalence increased with mass. although it occurred in both sexes, the a c e b d badgers removed in bro increase was much more pronounced in males. wounding was more frequent in adult males than in adult females, and adults had more wounds than juveniles. the highest rate of infection was seen in individuals with the most wounds. similarly, in rats (rattus norvegicus) hantavirus infection (seoul virus) was associated with both wounding and elevated testosterone levels (easterbrook and klein, ; easterbrook et al., a) . it is therefore evident that changes to social structure-for example, by the removal of a dominant male-could have important implications for the epidemiology of a disease. rather than attempt to control disease by vaccination or culling, an alternative approach is to understand the factors leading to disease outbreaks in the first place and to manage these (dobson, ) . habitat changes that lead to alterations in population structure or migratory patterns, for example, are likely to affect the risk of zoonotic disease transmission (dobson and may, ) . the effect of habitat fragmentation on disease processes has rarely been investigated, but it has recently been shown that trypanosoma cruzi infection rates are higher in fragmented than continuous atlantic forest (vaz et al., ) ; and the risk of lyme disease in new york is also apparently increased by fragmentation (allan et al., ) . interestingly, the division of endangered ethiopian wolf population into small sub-populations, joined by habitat corridors, has been shown to allow rabies control to be achieved using a low-coverage vaccination strategy (haydon et al., ) . the strategy operates by eliminating the largest outbreaks of disease, and so enhances meta-population persistence, rather than by the conventional objective of reducing the reproductive number of the disease to less than one (haydon et al., ) . human activities that artificially increase, rather than decrease, animal densities also influence disease processes. these increases can be the result of losses of absolute habitat area, or from the provision of supplementary food or water. in the united states, the practice of supplementary feeding of house finches and white-tailed deer has lead to an increase in the incidence of mycoplasmal diseases and btb, respectively (hartup et al., ; schmitt et al., ) , presumably because of greater opportunities for disease transmission, and possibly also immunosuppressive effects of aggression at the feeding sites. btb has also been an intractable problem in the british cattle herd, with the incidence rising inexorably since . with a cull of badgers recently being ruled out, somewhat controversially, as offering no meaningful contribution to the long-term control of the disease (donnelly et al., ) , it is worth asking whether consideration of the ecology of the badgers and cattle might help generate workable solutions. over the past years, along with the increase of btb, there has also been an increase in badger densities, and it is likely that this contributes at least in part to the disease in cattle. so why have badger populations risen? might the answer lie in changes in land use? macdonald and newman ( ) speculate on a possible role for climate change, with milder winters and hence greater earthworm availability improving survival rates. changes could also have occurred in the susceptibility of badgers to btb and/or of cattle to btb. for example, the average milk production of a dairy cow rose from , l in to , l in (farm animal welfare council, ) , possibly to the detriment of the animal's immune status. similarly, stress resulting from cull-associated social perturbations, or from other changes to habitat, food availability or population density, may have influenced the innate immune response of badgers. little is known of the physiological responses of free-living wild mammals to poor environmental quality or other potential stressors. an argument has been made for polychlorinated biphenyls (pcbs) and other pollutants contributing to phocine distemper outbreaks (ross et al., (ross et al., , , but this is has been questioned (o'hea, ) . while the role of toxicants is not clear, recent work indicates that high population densities in wild field voles is associated with compromise in haematological and immunological indices. poor body condition appeared to affect the inflammatory response (as indicated by lower neutrophil and monocyte peaks) and lower immunological investment (as indicated by lower lymphocyte counts (beldomenico et al., a,b) . i have found, with co-worker jon blount, preliminary evidence of increased oxidative stress (measured by serum malondialdehyde concentration) among non-infected badgers from farms with recent btb in cattle, compared with those at sites free of btb ( fig. . ). there is also a considerable literature from farm (moberg and mench, ) , laboratory (galloway and handy, ) , and free-living aquatic animals (liney et al., ) showing that environment has a strong impact on stress responses, and that these can lead to pathological and pre-pathological alterations in immune function and overall health status. while it might be difficult to intervene directly to reduce the causes of stress in animals, ecologically based interventions that reduce both disease susceptibility and the opportunities for transmission may be possible. for example, in a study of british farms it has been shown that habitat management and cattle herd size were strongly associated with the risk of btb in dairy cattle (mathews et al., a) . reduced risk of btb was associated with the management of farmland in ways favourable to wildlife, including greater hedgerow availability, a lack of gaps in hedgerows, increasing hedgerow width and the presence of ungrazed wildlife strips adjacent to hedgerows. all of these measures are encouraged by recent european common agricultural policy reforms ( ) . broadly, habitat could influence cattle contact rates or be associated with agricultural management practices in ways relevant to btb transmission (such as reduced herd size). favourable habitat may lower the susceptibility of badgers to btb or reduce the number of inter-group excursions; alternatively, cattle on hedgerow-rich farms may be at reduced risk of ingesting contaminated soil. taking for simplicity just one of the parameters contributing to the effects-the total length of hedgerow-an increase of km/ ha was associated with a decrease in the odds of btb by about . % ( % confidence interval . % increase to . % decrease) in univariate analysis. in absolute terms, this equates to the annual risk of btb changing from the current rate of . % ( , confirmed incidents in , herds in ) to . % ( , incidents) for herds in the west of england if a policy of moderate hedgerow density increase were adopted. this would mean a reduction of infected herds per year. by comparison, systematic badger culling appears able to reduce the odds of btb by a maximum of about % and may even increase the prevalence in neighbouring areas (donnelly et al., ) . change in land use has also been linked to the emergence of two henipaviruses, nipah virus and hendra virus in the s, and land use management may therefore offer part of the solution. both viruses appear to be asymptomatic in their natural hosts, fruit bats (genus pteropus). they are amplified in domestic animals, pigs and horses, respectively, where they cause mortality, and can then be passed on to humans (chua et al., ; halpin et al., ) . the closeness of rna sequence match between pteropus sp., livestock and human isolates of each virus suggests that a sudden change in virulence is a less likely explanation of their rapid emergence into domestic animals and humans than is the ecological change that have affected the habitat of their natural hosts. many flying fox species are in decline, with roosting and feeding sites being deforested, and converted to agricultural or urban use. a number of hypotheses have been proposed to explain exactly how nipah virus emerged (see breed et al., ) , all of which involve the establishment of piggeries in previously forested regions still used by fruit bats (chua et al., ) . increased contact rates are also the likely explanation for the emergence of hendra virus in australia, with many pteropus populations having relocated into urban areas (hall and richards, ) . with no vaccine available, and pteropus in need of conservation, ecologically based strategies to limit contact rates between bats and livestock offer the best prospects of controlling the disease (field and mackenzie, ) . managing the risks from zoonoses to the health of humans and domestic animals is complex. it is also fundamentally important: virtually all emerging infectious diseases have originated in wildlife. superficially, the simplest method of control is via a reduction in reservoir host-disease prevalence, this being achieved by culls of host populations. however, effective reductions in population densities can be difficult to achieve in practice and may be undesirable where the target is of conservation concern. for example, most bat species are threatened, and yet they appear to be particularly important sources of emerging viruses (calisher et al., ; 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culling on badger meles meles spartial organisation: implications for the control of bovine tuberculosis key: cord- -ew nraq authors: cipriano, l. e.; haddara, w. m. r.; zaric, g. s.; enns, e. a. title: impact of university re-opening on total community covid- burden date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ew nraq purpose: post-secondary students have higher than average contacts than the general population due to congregate living, use of public transit, high-density academic and social activities, and employment in the services sector. we evaluated the impact of a large student population returning to a mid-sized city currently experiencing a low rate of covid- on community health outcomes. we consider whether targeted routine or one-time screening in this population can mitigate community covid- impacts. methods: we developed a dynamic transmission model of covid- subdivided into three interacting populations: general population, university students, and long-term care residents. we parameterized the model using the medical literature and expert opinion. we calibrated the model to the observed outcomes in a mid-sized canadian city between march and august , prior to the arrival of a relatively large post-secondary student population. we evaluated the impact of the student population ( , people arriving on september ) on cumulative covid- infections over the fall semester, the timing of peak infections, the timing and peak level of critical care occupancy, and the timing of re-engaged social and economic restrictions. we consider multiple scenarios with different student and general population covid- prevention behaviours as well as different covid- screening strategies in students. results: in a city with low levels of covid- activity, the return of a relatively large student population substantially increases the total number of covid- infections in the community. in a scenario in which students immediately engage in a % contact reduction compared to pre-covid levels, the total number of infections in the community increases by % (from , without the students to , infections with the students), with % of the incremental infections occurring in the general population, causing social and economic restrictions to be re-engaged weeks earlier and an incremental covid- deaths. scenarios in which students have an initial, short-term increase in contacts with other students before engaging in contact reduction behaviours can increase infections in the community by % or more. in such scenarios, screening asymptomatic students every days reduces the number of infections attributable to the introduction of the university student population by % and delays the re-engagement of social and economic restrictions by week. compared to screening every days, one-time mass screening of students prevents fewer infections, but is highly efficient in terms of infections prevented per screening test performed. discussion: university students are highly inter-connected with the city communities in which they live and go to school, and they have a higher number of contacts than the general population. high density living environments, enthusiasm for the new school year, and relatively high rates of asymptomatic presentation may decrease their self-protective behaviours and contribute to increased community transmission of covid- affecting at-risk members of the city community. screening targeted at this population provides significant public health benefits to the community through averted infections, critical care admissions, and covid- deaths. the covid- pandemic presents a substantial public health challenge for local, national, and international communities because the virus is highly transmissible, - including prior to symptom onset, , and infections initially present with a wide range of non-specific and sometimes mild symptoms. , the relatively high rate of hospitalization and need for critical care among severe cases can quickly overwhelm community health care resources and result in substantial mortality. , many communities initially responded to covid- with school closures and stay-at-home orders, which included closure of university campuses and conversion of all in-person instruction to online formats. over the summer, universities began announcing plans for the fall term. some universities opted to operate fully online for the fall. others announced plans to partially or fully re-open campus and welcome students back for in-person instruction with covid- mitigation strategies in place. these strategies included polices around mask wearing, limiting large gatherings, access to covid- testing, reduced dormitory occupancy, and accommodations for isolating and quarantining students. while universities have the autonomy to make decisions about the level of on-campus activities offered to their students, their decisions have implications for the communities in which these campuses are located. university students live, work, and socialize both on and off campus, resulting in significant potential for on-campus covid- outbreaks to spill over into the community and vice versa. infectious diseases can spread rapidly through a university campus, as evidenced by outbreaks of serogroup b meningococcal disease, mumps, and the novel h n influenza virus that emerged in . , [ ] [ ] [ ] surges of covid- cases have already been observed on the first campuses to re-open this fall, prompting many universities to abruptly change their fall semester plans. after students tested positive for the novel coronavirus linked to at least four separate clusters, the university of north carolina abruptly moved all undergraduate classes online after only a week of in-person instruction. high-density housing, including multiple roommates and shared facilities like bathrooms, as well as high levels of social activity puts the university population at particular risk for infectious disease transmission. furthermore, past experience with the h n pandemic indicates compliance with recommended public health precautions may be sub-optimal; despite public health guidance not to attend classes and other activities while ill during the h n outbreak at a us university, half of students indicated interacting with a symptomatic individual in a classroom and nearly one-quarter indicated interacting with a symptomatic individual at a party or social activity. given the unique features of university communities, several studies have modeled covid- transmission dynamics specifically on university campuses and evaluated potential mitigation strategies. , [ ] [ ] [ ] [ ] [ ] these studies used mathematical models of viral transmission dynamics, tailored to reflect a university context, in order to evaluate testing and contact tracing strategies, largely focusing on the question of how frequently to test asymptomatic students. all analyses concluded that frequent testing (sometimes multiple times a week) would be needed to contain covid- outbreaks on campus. high frequency testing has been adopted by a number of public and private universities including, for example, the university of illinois (twice per week by saliva testing ), colby college (twice per week by nasopharyngeal swab ), cornell university (twice weekly for students and faculty with student contact by self-collected anterior nares sampling ) , and harvard university (one to three days a week for students, staff, and faculty by saliva testing with frequency depending on types of on-campus activity ). however, most universities do not have the resources or infrastructure to support high-frequency testing. furthermore, while some of these studies did include infections among students arising from offcampus community contact, these studies did not consider the impact of university student infections and university administration prevention and management decisions on the broader community in which that campus is situated. university students themselves may be at lower risk of severe covid- disease due to age, but high infection rates on campus may spill over into the broader community, whose members are at higher risk for adverse covid- outcomes. it is therefore important to quantify the expected impact of the arrival of a relatively large number of university students on the broader community in terms of incremental infections, hospitalizations, and covid- mortality. through the many interactions between the student population and the city in which they reside, covid- mitigation policies targeted at university student communities and adopted by university leaders may have substantial public health implications for those in the surrounding community. we developed a dynamic transmission model of covid- to estimate the health impacts and health care resource demand in a covid- outbreak in a representative mid-sized city with a relatively large destination college campus. we assumed a city experiencing a low level of covid- activity going into the semester and explore how the on-campus arrival of the student population impacts covid- health outcomes in the community. we consider different assumptions about student behaviours related to physical distancing and mask wearing, as well as the mitigating effects of targeted routine and one-time covid- screening in the university population. we developed a dynamic compartmental model to simulate infection dynamics and health resource use of a representative mid-sized city with a population of , going into fall after experiencing low rates of covid- infections in the summer. we divided the population into three sub-populations: long-term care (ltc) residents, university students, and the general population (everyone other than ltc residents and university students). we evaluated covid- health outcomes in the city between august and december ( . months) with and without the introduction of , university students on september . we explored how the covd- risk and prevention behaviours of the general population and the student community affect the incremental covid- burden attributable to the arrival of the student population. under different scenarios of community physical distancing effort and routine testing in students, we calculated the number of infected individuals, peak hospital resource demand, and number of deaths over time. institutional ethics review was not required for this modeling study as human subjects were not involved. a schematic of the model is presented in figure . in the model, susceptible individuals may become infected through interaction with infected individuals who may or may not be aware of their infection status. infection has a pre-symptomatic phase in which an infected individual can transmit the infection to others. , , individuals may become aware of their infection status through symptom-based surveillance, contact tracing, or routine testing of asymptomatic and mildly symptomatic individuals. individuals aware of their infection status with mild or moderate symptoms isolate at home to reduce disease transmission. some patients develop severe symptoms requiring hospitalization or critical symptoms requiring mechanical ventilation (mv) in an intensive care unit or renal replacement therapy (rrt). patients receive medically indicated care, unless resource demand exceeds capacity. when hospital capacity for a medically indicated resource has been reached, patients receive the next-best available care. we estimated model parameters, including the duration of time spent in each health state, the infectiousness of covid- , demand for hospital resources and disease mortality conditional on disease severity, and the effectiveness of covid- prevention strategies using the peer-reviewed literature, pre-published reports, and expert opinion ( table ) . we calibrated uncertain model inputs to the observed hospitalization and mortality outcomes in london, ontario, canada, a mid-size city with a large university population, between march to august . full details about the model structure and input parameter estimates are presented in the supplemental methods. we first establish the epidemic starting conditions in the city on august before the potential arrival of students for fall semester. based on calibration to covid- outcomes in london, on, at the start of the simulation, individuals in the general population had active covid- infections, . were exposed but not yet infectious, and , individuals had already recovered; thus, , individuals were susceptible at the beginning of the simulation. in sensitivity analysis, we vary the number of active covid- infections in the general population at the start of the simulation. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint in our analysis, . % ( , individuals) of the population live in long-term care (ltc). based on the model calibration we estimated that ltc residents were recovered as of august . we assumed that there were no active infections in ltc residents on august . we assume that , university students arrive on september . in the base case, we conservatively assume that no students are infected with covid- upon arrival to campus. we vary this assumption in sensitivity analysis. a schematic of the health states and transition times for infected individuals is presented in appendix figure . we assumed a mean incubation period, the time from exposure to symptom-onset, of . days (observed median of . days [ %ci . , . ]). in total, we estimated the average duration of infectiousness in asymptomatic and mild or moderate infections to be days, including . days prior to symptom onset in individuals who do become symptomatic. , , we assumed that patients with severe and critical symptoms remain infectious until recovered, but that patient isolation protocols prevent transmission for those admitted to hospital. we estimated hospital length of stay and mortality based on a report of over , hospitalized patients in the uk. we estimated length of stay and mortality for patients receiving critical care using the uk intensive care national audit and research centre report describing the care and outcomes of , critical care covid- patients. for ltc residents who are and are not hospitalized, we estimated the case fatality rate to be . % and . %, respectively, based on the observed outcomes in canadian ltc covid- patients. combining the assumptions about disease severity and severityspecific mortality rates, the overall infection fatality rate in our model was . % for ltc residents, . % for the general population, and . % for university students. among hospitalized cases, the fatality rate was . % for the general population, and . % for university students. we did not consider mortality from causes other than covid- in the model. general population: based on an extrapolation of the polymod study in europe to reflect network structure of the canadian population, the average number of contacts per person in canada is . per day, of which . contacts is aged - . assuming that the university student population adds , individuals aged - to a community with an otherwise typical canadian age distribution, university students would comprise % of the population of people aged to in the community. as a result, we assume that a person in the 'general population' has contact with . university students per day. we calculated the average number of ltc contacts by calculating the number that would balance the staff and visitor contacts estimated for ltc residents, resulting in . ltc contacts per person in the general population. long-term care residents: we estimated that there are . resident-resident contacts per day ( % ci: . - . ) and . resident-staff contacts per day ( %ci: . , . ) using a canadian study of longterm care residents and staff (personal communication: s. moghadas). , this study did not capture . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint resident-visitor contacts; we assumed . visitors per day based on the distribution of visit frequency in the ohio nursing home family satisfaction survey. thus, in total, ltc residents have . contacts with the general population each day. we assumed no direct contact with university students. university students: in our base case analysis, we assume that students have . contacts per day, based on a study at the university of antwerp, and that % of those contacts are with other university students based on the age distribution of student's reported contacts, , with the remainder being with members of the 'general population' which includes staff and faculty of the university. because studies evaluating university student contact patterns often occur during late fall and winter months, the contact patterns identified may not be fully representative of student contact rates at other times of the year. in sensitivity analysis we explored higher rates of student-student contacts in the first few weeks of the semester. using exponential regression, we empirically estimated a basic reproduction number, r , of . in the general population based on ontario's reported cases between march to march . using an average duration of infectiousness of days and an average number of close contacts per person of . , we calculate the probability of transmission between a susceptible and an infected person in close contact, in the absence of any interventions, to be . . interventions such as physical distancing, which reduces the average number of contacts between susceptible and infected people, and mask wearing, which reduces the probability of disease transmission between contacts, can reduce the expected number of infections. we assume the effectiveness of cloth masks in reducing disease transmission is % based on a german study evaluating the effectiveness of real-world mask use. for people who are aware of their infection status and in home isolation, we assume a % reduction in contacts, which is at the high end of observed adherence to quarantine instructions in past epidemics. , we subdivided the general population into two groups based on their intensity of covid- prevention behaviours. based on behaviours reported in an angus reid poll of canadians, taken in the first week of august, we estimated that 'high-intensity physical distancers', representing % of the general population initially, reduce their average number of contacts by % (from . to . contacts per day) and that % of their remaining contacts are protected by a cloth mask. we assumed that the remainder of the population are not reducing their contacts, but are using a cloth mask to protect % of those contacts. in the base case, we assumed that university students initially reduce their contacts by % (from . to . contacts), which approximates a % reduction in contacts for the % of - year-olds who reported substantial covid- prevention effort in the angus reid poll ( % x % = % reduction). in this same survey, % of - year-olds reported wearing a mask indoors with people outside their household and we use this as the base case level of mask wearing in the university student population. responsive behaviour triggers: we assumed that the general population and university students respond to covid- outcomes in the community. in practice, this response may be voluntarily adopted due to public concern over reported increases in covid- cases, hospitalizations, and/or deaths or . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint imposed through policies that re-establish the social and economic restrictions utilized in the earlier phases of the pandemic. we included two triggers that would cause both the general population and university students to increase their adoption of protective behaviors: a high level of covid- patients in critical care and a high number of covid- deaths. the critical care trigger was set based on critical care capacity. the overall critical care capacity in ontario is . beds per , population. thus, in a city of , , normal critical care capacity would be about beds. while additional capacity can be created by seconding resources and personnel from other hospital services, based on expert opinion, substantial reductions in the provision of other types of health care (such as cancelling elective surgeries) would need to be undertaken if more than critical care beds were used by covid- patients. therefore, we set one of the responsive behaviour triggers to activate when there are covid- patients in critical care, representing % of the capacity available to covid- patients without modifying access to other health care services. in the base case, the proportion of the general population who are 'high intensity physical distancers' increases by . % each day if the number of covid- patients in critical care exceeds and by an additional . % each day if the number of covid- deaths in the past days exceeds , up to a maximum of % participation in high-intensity physical distancing. similarly, we assume students' reduction in contacts increases at the same rate in response to the same triggers, but up to a maximum of a % reduction in contacts ( . contacts to . contacts). for the general population and university students, we assumed the minimum time from symptom onset to diagnosis to be . days, which is consistent with the minimum time needed to self-assess, seek medical attention, and receive diagnostic results. the observed median time to diagnosis through symptom-based surveillance alone was . days ( %ci: . , . ) and symptom-based surveillance in combination with contact tracing efforts was . days ( %ci . , . ) in shenzhen, china. from this, we estimated that symptom-based surveillance and contact tracing results in a daily probability of diagnosis of . % for symptomatic infections and a daily probability of detection (from contact tracing) of . % for asymptomatic infections. this combination of assumptions resulted in approximately % of infected individuals being identified, consistent with the overall rates of diagnosis implied by preliminary serology data in ontario. we considered policy alternatives of routine screening for covid- in university students at various screening frequencies, including every , , , , and days. we also considered the value of a onetime universal screening three weeks after student arrival. we identified the date of the one-time testing by identifying the date that minimized the number of total infections over the semester. we assumed that testing will be performed with the standard covid- nasopharyngeal swab followed by pcr analysis with a test sensitivity of . %. , . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint without the introduction of the student population, the base case assumptions for the general population and ltc residents leads to a total of , infections over . months (august to december ). in this scenario, infections, hospitalizations, and daily deaths do not peak until the new year (appendix table ). demand for critical care (mechanical ventilation or renal replacement therapy) peaks at beds early in the new year, and a total of covid- deaths occur between august and december ( deaths by january , ). the timing and magnitude of the city's covid- outbreak, excluding any impacts from students, is determined by the initial number of covid- infections in the community, the level of participation in physical distancing, the responsiveness of the community to increasing critical care cases and covid- deaths, and the proportion of contacts that are protected with mask wearing (appendix figures - ) . in the base case, we conservatively assumed that students would bring no undiagnosed infections of covid- to the community and would immediately engage in physical distancing efforts that resulted in a similar average contact reduction to the general population (reduction of %, from average of . contacts to . contacts). even so, university students continue to have a higher average number of contacts than members of the general population. as a result, in this base case scenario, the introduction of students to the community increases the total number of infections by , infections, representing an % increase (from , to , ) (figure ) . only % ( ) of these incremental infections occur in the student population (representing . % of students becoming infected). of the remaining % of incremental infections, , occur in the general population ( . % of the susceptible general population), and occur in long-term care ( . % of the susceptible ltc population). the larger absolute increase in infections in the general population occurs due to the connectivity of the university community with the general population and the relative size of the general population. the increase in infections among ltc residents, despite our assumption that there are no direct contacts between university students and ltc residents, occurs due to the increase in infections in the general population. the higher number of infections results in an increase in hospitalizations, demand for critical care, and covid- deaths. peak critical care occupancy increases by % (from to beds). these outcomes include the mitigation effects of the responsive behaviour of the community to seeing high levels of covid- hospitalizations. the introduction of students to the community also moves up the timing of responsive behaviours, with the threshold of covid- patients in critical care being reached weeks earlier (appendix table ). if some students arrive exposed or asymptomatically infected, the total number of infections occurring over the course of the semester increases. for example, if students arrive infected, the number of infections increases by , over the base case. the impact of students arriving already exposed or infected in the community is most substantial on the timing of peak infections, peak hospitalizations, peak critical care utilization, and the timing of responsive behaviour triggers. compared to the scenario without the introduction of the student population, responsive behaviours are triggered . weeks earlier if students are infected when they arrive (appendix table ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint our estimates of average student contacts per day were based on surveys completed at times other than during the first few weeks of the school year, which normally involve a large number of social activities. even if muted, the first few weeks of the new academic year may still result in substantially more contacts than a typical pre-covid era day. therefore, we explored the consequences associated with students having an increased number of student contacts for one or two weeks upon arrival to the community. for example, if students simply delay implementing physical distancing for two weeks, the total number of infections attributable to the introduction of the students into the community increases by , infections (from , to , infections). in this scenario, the arrival of students would result in a % increase in the number of infections the community. as in the base case, the majority of these incremental infections occur in the general population (figure ). if students have twice the pre-covid era number of contacts with other students for two weeks ( . contacts per day, . of whom are other students), the total number of infections in the community increases by , infections representing a % increase in the number of infections the community would expect without the students and leading to an additional covid- deaths (appendix figure , appendix table ). delays in the implementation of contact reductions, or short-term increases in the number of student-student contacts increases demand for critical care resources and shortens the time until critical care beds dedicated to covid- patients exceeds beds (figure b) . the impact on total infections is mitigated by the earlier activation of responsive behaviour triggers, which occurs . weeks after the arrival of the students and weeks earlier than without the arrival of the student population. because young people have a high rate of asymptomatic and mild presentation, routine testing of students has been proposed for university campus settings. testing students every days results in very little reduction in the number of infections but requires a large number of tests ( students tested per day). testing every days, as is recommended for staff at long-term care facilities, reduces the number of infections in the student population from to , a % reduction, and reduces the overall number of infections due to the introduction of the university student population by % (from , to , ) (figure ) . more frequent testing reduces infections further. testing students every days reduces the number of infections among the student population by % (from to ) and reduces the total number of infections due to the introduction of the university student population to the community by % (from , to , ). routine testing has greater impact in the scenarios when students engage in a shortterm increase in the number of contacts early in the term. in the scenario in which students double their student contacts for the first two weeks of term, testing every days reduces the number of infections in the student population by % (from , to , ), reduces the total number of infections due to the introduction of the university student population by % (from , to , ), and delays the activation of responsive behaviour triggers by week (appendix table ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint routine testing of students also averts critical care admissions and covid- mortality in the general population, because approximately two-thirds of averted infections are prevented in the general population ( table ). in the base case analysis, in which students immediately reduce their contacts compared to a pre-covid- , routine screening every days averts . critical care admissions and . deaths. in scenarios in which students have short term increases in their contact behaviours or lower levels of contact reduction, routine testing every days averts more than critical care admissions and greater than covid- deaths. sensitivity analysis revealed that routine testing of university students was more valuable when students have a higher rate of asymptomatic infections ( table ) and in scenarios in which the differences in transmission risk between the university students and the general population were greater. for example, in a scenario in which the city had a high level of engagement in physical distancing routine screening of the student population can avert a large number of infections because in these scenarios the city expects very little covid- transmission without the introduction of the student population ( figure c) . conversely, in scenarios in which the city is engaged in a low level of physical distancing and so expects a large number of infections with or without the student population, the difference in risk profile between the city and the university populations decreases, as does the benefits of targeting prevention efforts at the university population. routine testing to identify and isolate asymptomatic infections for the purposes of reducing community transmission risk requires a large number of tests each day and may strain community testing resources. we also evaluated the benefits of a one-time universal screening event occurring three weeks after the students arrive. compared to routine testing every days, which would require more than , tests to be performed over the semester, this strategy would only require , tests. through the isolation of identified cases, one-time testing is able to immediately decrease the daily number of new infections in the student population and, so, indirectly in the general population (appendix figure ). in the case that students double their contacts with other students for a period of two-weeks, this strategy prevents infections ( infections in students, infections in the general population, and infection in ltc residents), . critical care admissions, and . covid- deaths ( table ) . one-time screening does not significantly impact the timing of peak infections, resource utilization, or the time that responsive behaviour triggers are activated (appendix table ). we performed extensive sensitivity analysis exploring the impact of general population and student population covid- prevention behaviours on the incremental impact of introducing students into the community. the negative impacts of introducing the student population can be partially mitigated through high uptake of covid- preventive behaviours in the student population including high rates of contact reduction or if the rate of mask wearing significantly exceeds the level reported by to year-olds (appendix figure , appendix table ). for example, if students immediately reduce their contacts by, . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint on average, % (from . to . contacts per day) and wear masks to protect % of their remaining contacts, the incremental number of infections attributable to the arrival of the student population can be reduced to , infections (from , to , ), representing only a % increase over the number of infections the community would expect without the students, and delays the activation of responsive behaviour triggers by week. the magnitude of the impact of the introducing the student population is also determined by the covid- prevention behaviours of the general population. counter-intuitively, the relative impact of introducing the student population is greatest when the prevention efforts by the general population are high (appendix figure ) . for example, when % of the general population are participating in high-intensity physical distancing, without students the number of new infections per day is nearly constant over time, resulting in a very low level of cumulative infections over the semester (total of infections). introduction of the students results in additional infections, more than doubling the total number of infections expected in the city without the addition of the student population (appendix table ). in such a scenario, because the student population is an important determinant of city outcomes, the impact of routine covid- screening in the student population is greater ( figure c ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint in this analysis, we consider the covid- impacts of the re-opening of a destination university in a midsized city with varying epidemiological contexts. without the return of university students, we devised several scenarios involving moderate to severe fall covid- waves based on difference levels of preventive behaviours in the general population. the return of a large number of students always worsens these waves, even under the conservative assumptions that arriving students do not introduce any new infections to a community and that they immediately adopt substantial covid- prevention behaviours. this is because university students have nearly double the number of contacts as the general population due to residing in shared or congregate living situations, working in the service sector, and higher levels of social activity. in the scenarios we considered, this increase in infections was substantial, potentially doubling of the total number of covid- infections in the city over the fall. notably, we found that more than two-thirds of the incremental infections attributable to the arrival of the student population occurred in the general population and, as a result, substantially impacted the city's health care resource needs, covid- mortality in the community, and accelerated the need for responsive behaviour which may be in the form of re-engaged social and economic restrictions. our base case finding that the return of university students would increase the number of infections by % is likely conservative. in this analysis, we assumed that no students arrive already infected, students do not engage in short term increases in contacts upon arrival, and that students respond to adverse community covid- outcomes by increasing the intensity of their prevention behaviours at the same rate as the general population. at the very least, it may take time for students to fully adopt protective measures; moving into dorms, orientation events, and start of semester social events (even if not officially sanctioned by the university) may result in higher-than-normal levels of contact for at least the first few weeks. in the analyses in which we consider short-term increases in the average number of student-student contacts, we show that a higher level of contact for just the first one or two weeks can dramatically increase the total number of infections experienced by the city over the semester. our analysis found that the majority of the increase in infections due to the arrival of students occurred in the general population, not in the student population itself. while university campuses may seem like isolated bubbles, the general community and university students are intertwined, as staff and faculty interact with students on campus and students interact with others off-campus in work, living, and social settings. previous studies modeling university populations did not account for infections in the broader off-campus community. [ ] [ ] [ ] [ ] [ ] however, we have shown that including the general population when modeling covid- transmission on university campuses is critical, since this population bears the brunt of the incremental morbidity and mortality burden of covid- . as a result, university policies that either discourage student return to the community, such as offering coursework fully online, or mitigate covid- risks for students returning to campus, such as screening for covid- symptoms and routine covid- testing in asymptomatic individuals, can have substantial impacts on the city's covid- burden. imposing restrictions on students' off-campus social behavior may be practically difficult, necessitating modified behaviors in the general population in response to university reopening, such as additional reductions in social contacts to balance the increased risk of returning university students. for example, in the base case, the increase in infections due to student arrival could be mitigated if the proportion of the general population engaged in high-intensity physical distancing increased by . % (from % to . %). this illustrates the idea of "risk budgets", where increased risk . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint in one domain of a community necessitates reducing risk in another to keep covid- impacts below desired thresholds. our analysis indicates that routine testing of all students every days can avert a substantial number of infections, critical care admissions, and covid- deaths. in the base case, we estimate that testing every days prevents . critical care admissions and . deaths and, in the scenario in which students double their contacts with other students for two weeks, we estimate that testing every days prevents . critical care admissions and . deaths. using the simplifying assumption that all deaths averted will be in -year-olds and a willingness to pay of $ , per life-year-gained, the economic value of these deaths averted is $ . million to $ . million, translating to a value of $ to $ per test. this calculation underestimates the benefits of testing by not accounting for savings due to averted critical care admissions and the community economic benefits of delaying social and economic restrictions; despite this, because we estimate the lab cost of nasopharyngeal testing for covid- at $ per test at our center, high-frequency routine testing is likely only cost effective using batch testing strategies. alternatively, one-time universal testing of students after an initial burst of social activity among students may be more feasible operationally and economically. we estimated that this strategy can prevent infections, . critical care admissions, and . covid- deaths corresponding to an approximate economic value of $ . million or $ per test. this strategy is most effective at changing the trajectory of new infections if testing occurs after a short-term period of high social activity and is less effective if students have consistent but lower levels of contact reductions (e.g., immediately reducing their contacts, but by only % instead of the % in the base case). an important limitation of our analysis is that we assume students with a covid- diagnosis will be willing and able to self-isolate effectively. however, it may be challenging for students to isolate from roommates or refrain from using shared facilities, like bathrooms and kitchens, without dedicated university-organized isolation facilities. , furthermore, adherence to isolation guidance may be low, especially if the majority of infections in university students are asymptomatic or mild. during the h n pandemic, a survey of symptomatic university students found that only % of students followed recommendations to stay home until well. in the base case, we also assume that students are equally responsive as the general population to covid- outcomes in the community reducing their contacts in response to high numbers of critical care hospitalizations and deaths. in reality, university students may be less aware of the impacts of covid- on hospital resources and less concerned about covid- generally given their lower risk of adverse outcomes. the extent and speed with university students respond to hospitalizations and deaths in the local community will impact the number of infections experienced by the community and the benefits of routine testing in the student population. compared to other modeling studies of covid- on university campuses, the total number of infections and the number of infections averted by testing we estimate over the semester are modest. this is because we assume that both university students and the general population will increase their self-protective behavior (physical distancing) in response to high numbers of covid- hospitalizations and deaths, either through individual decision-making or adaptive community policies. these adaptive behaviors are more realistic than assuming a population will maintain the same behavior no matter the severity of local covid- conditions. thus, in our analysis, testing is being layered onto a robust and reactive mitigation response. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint our model includes only three sub-populations and so does not include many other aspects of agestructured mixing or age-dependant health outcomes. the model does not estimate the impact of covid- patient utilization on the provision or effectiveness of other health care services and the model does not account for death from causes other than covid- . the model includes community transmission by stratified random mixing but does not include additional imported index cases from other cities, which may occur into the general population or the student population, nor does the model include the stochastic consequences of super-spreading events. especially early on in an epidemic or when cases have been brought to very low levels, dynamics are sensitive to random outcomes in the number of new infections resulting from each case (e.g., 'patient ' in south korea and 'patient one' in italy ). we developed a model-based analysis to estimate the impact of a relatively large student population on the covid- outcomes of a mid-sized city with relatively few cases of covid- prior to the return of students. our analysis is relevant to a number of mid-sized cities in north america with relatively large university and college populations. because university students have substantially more contacts than the general population, due to congregate living environments, high-density social activities, and disproportionate employment in the service sector, the introduction of university students substantially increases the number of covid- infections and decreases the time until responsive behaviours are activated. substantial uncertainty exists in the level of contact reduction that students will choose, or is feasible given their living, transit, and work situations. public health interventions, such as routine testing, targeted at this population prevents infections in the entire population, improving community health related and unrelated to covid- . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint figure . model schematics of (a) covid- health states and (b) close contact interactions between population subgroups. the number of contacts between groups indicated on the schematic represent the average number of contacts per day in a pre-covid- era. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. table . end of the two-week burst in contacts. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . in panel (a), students have an average % reduction in contacts compared to normal student social interaction behaviour (average of . contacts reduced to . contacts) immediately upon arrival with no shortterm increase in contacts; in panel (b), students double their contacts with other students for the first two weeks and then implement a % reduction in their contacts; in panel (c), students double their contacts with other students for the first two weeks and then implement a % reduction in contacts and % of the general population is participating in high-intensity physical distancing (compared to % in the base case and other scenarios presented in this figure). other outcomes for these scenarios are reported in appendix table . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint from this, we estimated that symptom-based surveillance and contact tracing results in a daily probability of diagnosis of . % and the daily probability of detection from contact tracing of . % in asymptomatic infections. c. among critical care patients, we estimate the ratio of patients requiring renal replacement therapy (rrt) to mechanical ventilation (mv) based on the uk intensive care national audit and research centre (icnarc) report describing the care and outcomes of , critical care covid- patients in the uk. in this report, , patients required mv and , required rrt, resulting in a ratio of . rrt patients per mechanical ventilation patient. d. in canada, based on , covid cases in people who were not residents of long-term care facilities reported between february and june , . % of hospitalized patients received critical care; this is also consistent with rates of critical care observed in the uk ( % overall hospitalized patients go to icu). therefore, we estimate the ratio of . hospitalized without critical care patients per critical care patient. e. initially estimated using the same process as is described in footnote d. adjusted in calibration process to better fit the observed data (see supplemental methods). f. median and iqr presented in the cited primary work were transformed to mean ( %ci range) assuming a gamma distribution. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint table . infections averted in the general population with -day testing and one-time testing of students compared to a policy of no routine asymptomatic testing (symptom-based surveillance and contact tracing only). scenarios vary the proportion of infections in the student population that are asymptomatic and timing and level of students contact reductions. we calculate the expected number of critical care admissions averted and covid- deaths averted to be . % and . % of general population infections averted which includes hospitalizations and deaths which may occur after december to all individuals infected prior to december . one-time testing three weeks after student arrival compared to no routine testing . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint high contagiousness and rapid spread of severe acute respiratory syndrome coronavirus pattern of early human-to-human transmission of wuhan early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia temporal dynamics in viral shedding and transmissibility of covid transmission interval estimates suggest presymptomatic spread of on behalf of the oxford covid- evidence service team. in patients of covid- , what are the symptoms and clinical features of mild and moderate cases? : centre for evidence-based medicine report : symptom progression of covid- . imperial college london covid- response team baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study us centers for disease control and prevention. considerations for institutions of higher education extensive geographical mixing of human h n influenza a virus in a single university community college campus outbreaks require timely public health response how the h n influenza epidemic spread among university students in japan: experience from shinshu university transmission of pandemic influenza a (h n ) at a public university--delaware non-pharmaceutical interventions during an outbreak of pandemic influenza a (h n ) virus infection at a large public university schools briefing: university outbreaks and parental angst college professors made models showing how bad covid- would be on campus. some administrators ignored them outbreaks drive u.n.c. chapel hill online after a week of classes. the new york times assessment of sars-cov- screening strategies to permit the safe reopening of college campuses in the united states covid- mathematical modeling for cornell's fall semester high covid- transmission potential associated with re-opening universities can be mitigated with layered interventions entry screening and multi-layer mitigation of covid- cases for a safe university reopening colleges plan for coronavirus testing, but strategies vary. wcvb news covid- and reactivation planning: surveillance testing coronavirus testing & tracing: unobserved self-administered testing risk for transportation of novel coronavirus disease from wuhan to other cities in china the incubation period of coronavirus disease from publicly reported confirmed cases: estimation and application virological assessment of hospitalized patients with covid- features of uk patients in hospital with covid- using the isaric who clinical characterisation protocol: prospective observational cohort study statistics canada. detailed preliminary information on confirmed cases of covid- (revised), public health agency of canada projecting social contact matrices in countries using contact surveys and demographic data the effect of individual movements and interventions on the spread of influenza in long-term care facilities individual movements and contact patterns in a canadian long-term care facility the predictors of and motivations for increased family involvement in nursing homes social mixing patterns for transmission models of close contact infections: exploring self-evaluation and diary-based data collection through a web-based interface who mixes with whom? a method to determine the contact patterns of adults that may lead to the spread of airborne infections ontario ministry of health and long-term care. covid- case data face masks considerably reduce covid- cases in germany changes in contact patterns shape the dynamics of the covid- outbreak in china how to improve adherence with quarantine: rapid review of the evidence covid- compliance: one-in-five canadians making little to no effort to stop coronavirus spread critical care readiness: expanding nursing staff to support covid- epidemiology and transmission of covid- in cases and of their close contacts in shenzhen, china: a retrospective cohort study blood tests indicate one per cent of ontario's population had covid- variation in false-negative rate of reverse transcriptase polymerase chain reaction-based sars-cov- tests by time since exposure comparative accuracy of oropharyngeal and nasopharyngeal swabs for diagnosis of covid- . centre for evidence-based medicine ontario ministry of health and long-term care. covid- testing for long-term care home staff winter term will be online: provost's letter close the bars. reopen the schools. vox college quarantine breakdowns leave some at risk. the new york times a university had a great coronavirus plan, but students partied on. the new york times delayed access or provision of care in italy resulting from fear of covid- the korean clusters. reuters graphics updated coronavirus: inquiry opens into hospitals at centre of italy outbreak the guardian outbreak investigation of covid- among residents and staff of an independent and assisted living community for older adults in infections in residents of a long-term care skilled nursing facility asymptomatic sars-cov- infections: a living systematic review and meta-analysis probability of symptoms and critical disease after sars-cov- infection effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients acute renal failure in intensive care units--causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. french study group on acute renal failure key: cord- -w k pdu authors: ojosnegros, samuel; agudo, rubén; sierra, macarena; briones, carlos; sierra, saleta; gonzález- lópez, claudia; domingo, esteban; cristina, juan title: topology of evolving, mutagenized viral populations: quasispecies expansion, compression, and operation of negative selection date: - - journal: bmc evol biol doi: . / - - - sha: doc_id: cord_uid: w k pdu background: the molecular events and evolutionary forces underlying lethal mutagenesis of virus (or virus extinction through an excess of mutations) are not well understood. here we apply for the first time phylogenetic methods and partition analysis of quasispecies (paq) to monitor genetic distances and intra-population structures of mutant spectra of foot-and-mouth disease virus (fmdv) quasispecies subjected to mutagenesis by base and nucleoside analogues. results: phylogenetic and paq analyses have revealed a highly dynamic variation of intrapopulation diversity of fmdv quasispecies. the population diversity first suffers striking expansions in the presence of mutagens and then compressions either when the presence of the mutagenic analogue was discontinued or when a mutation that decreased sensitivity to a mutagen was selected. the pattern of mutations found in the populations was in agreement with the behavior of the corresponding nucleotide analogues with fmdv in vitro. mutations accumulated at preferred genomic sites, and dn/ds ratios indicate the operation of negative (or purifying) selection in populations subjected to mutagenesis. no evidence of unusually elevated genetic distances has been obtained for fmdv populations approaching extinction. conclusion: phylogenetic and paq analysis provide adequate procedures to describe the evolution of viral sequences subjected to lethal mutagenesis. these methods define the changes of intra-population structure more precisely than mutation frequencies and shannon entropies. paq is very sensitive to variations of intrapopulation genetic distances. strong negative (or purifying) selection operates in fmdv populations subjected to enhanced mutagenesis. the quantifications provide evidence that extinction does not imply unusual increases of intrapopulation complexity, in support of the lethal defection model of virus extinction. rna viruses replicate as mutant distributions termed viral quasispecies. this is a consequence of high mutation rates operating during rna genome copying, due to the absence of proofreading-repair activities in the relevant rna-dependent rna polymerases and rna-dependent dna polymerases [ , ] . most phylogenetic relationships among rna viruses have been established using the consensus (or population) genomic sequences that represent a weighted average of multiple, closely related sequences present at each time point, in each virus sample obtained for analysis [ ] . phylogenetic relationships established with consensus viral sequences have been instrumental to classify viruses and to determine origin of emergent viruses and rates of virus evolution [ , , ] . for many purposes it is important to analyze phylogenetically the relationship among different genomes from the same mutant spectrum of a viral quasispecies. this type of analysis may reveal the existence of genome subpopulations within mutant spectra that might encode different phenotypic traits. also, it allows the calculation of average genetic distances among individual components of the mutant spectrum, a parameter that can be a predictor of biological behaviour [ ] . as an example, a study with a poliovirus mutant which displays a - -to -fold higher template-copying fidelity than the wild type documented that a narrow mutant spectrum impeded the virus to reach the brain of susceptible mice and produce neuropathology [ , ] . an early study documented that complexity of the coronavirus murine hepatitis virus quasispecies influenced the pathogenic potential of this virus for mice [ ] . a broad hepatitis c (hcv) virus mutant spectrum was associated with poor response to treatment by ribavirin and interferon α [ ] , and rapid early evolution of the virus led to a chronic infection [ ] . some studies have found an association between a reduction of mutant spectrum complexity of hcv at early stages of treatment and viral clearance ( [ ] ; reviewed in [ ] ). recently, the role of the mutant spectrum in adaptation of west nile virus has been documented [ , ] . therefore, there is a need to develop methods to describe the relationship among components of mutant spectra in viral populations. an estimate of the complexity and internal relationships among genomes within a mutant spectrum can be obtained through application of distance-based phylogenetic methods, such as neighbour-joining (nj) [ ] or maximum likelihood [ ] procedures. however, the reliability of the derived genome clusters may be questionable when the number of mutations distinguishing different components of a mutant spectrum is small. small genetic distances among genomes of a mutant spectrum are found when a viral clone (single genome) has undergone a limited number of passages in cell culture [ ] . despite this limitation, the general topology of a nj tree may be robust enough to provide information about the evolutionary pattern undergone by the viral population. an alternative method developed to group closely related sequences is partition analysis of quasispecies (paq), which is considered a non-hierarchical clustering method [ ] . paq groups together the viral sequences separated by the shortest genetic distances. for this purpose a centre genotype that nucleates a group of sequences within a circle (cluster) with a previously set radius is selected. high compactness of a group is defined by having a larger number of variants near the centre of the circle than at its boundary. in this fashion, multiple, overlapping or nonoverlapping groups can be defined within mutant spectra of viral quasispecies. paq has been successfully used to analyze subpopulations of equine infectious anemia virus [ ] , ty -copia retrotransposon sequences [ ] , regulatory sequences of bovine viral diarrhoea virus [ ] , and sequential isolates of hepatitis a virus [ ] . paq should find increasing application to describe viral quasispecies in view of its power to quantify relationships among related sequences, and of the critical role of mutant spectra in virus behaviour. our laboratory has studied quasispecies dynamics and evolution of foot-and-mouth disease virus (fmdv), a widespread picornavirus pathogen that causes the economically most important animal viral disease (reviews in [ , ] ). the molecular epidemiology of fmdv has been analyzed in detail by establishing an extensive database of genomic nucleotide sequences, as well as by defining phylogenetic relationships among and within serotypes and subtypes of the virus [ ] [ ] [ ] . fmdv has been used as a model system to investigate lethal mutagenesis, a term coined to describe virus extinction through an increase of viral mutation rate during replication ( [ ] ; reviews in [ ] [ ] [ ] ). studies on the interference that mutated fmdv and lymphocytic choriomeningitis virus (lcmv) populations exert on the infectivity of the corresponding standard genomes [ ] [ ] [ ] [ ] led to the proposal of the lethal defection model of virus extinction [ ] . according to this model, extinction can occur with a modest average number of mutations per genome that generates a class of genomes termed defectors, that can replicate but interfere with replication of the standard genomes [ , ] . defector genomes differ from defective-interfering (di) particles described for many viruses [ ] in that di particles are dependent on helper virus for replication while defectors are replication-competent [ , ] . in the course of the studies on lethal mutagenesis of fmdv, biological clones of the virus were subjected to serial cytolytic passages in cell culture in the absence or presence of the mutagenic bases or nucleoside analogues -fluorouracil (fu), ribavirin ( -β-d ribofuranosyl- , , -triazole- carboxamide) (r), or -azacytidine (azc) [ , [ ] [ ] [ ] [ ] . these treatments have provided a number of viral populations differing in their mutant spectrum complexity, as measured by the average mutation frequency and shannon entropy within mutant spectra [ ] [ ] [ ] [ ] [ ] . however, possible alterations of phylogenetic relationships among components of the mutant spectra of mutagenized quasispecies have not been studied. to characterize possible changes among components of fmdv mutant spectra as a result of the mutagenic treatments, here we compare phylogenetic and paq analyses of several multiply-passaged fmdv populations, and their mutagenized counterparts. the results show that phylogenetic and clustering methods can provide a quantification of the mutagenic activity exerted on viral populations by reflecting changes in genetic distances among components of the mutant spectra of the viral quasispecies. paq analysis describes mutant distributions as spheres with size which is proportional to the genetic diversity, which varies as a result of enhanced mutagenesis. this type of representation has revealed that viral populations can respond rapidly to environmental changes, with striking switches between relaxation and compactness of the population diversity, that were not apparent from the comparison of mutation frequencies or shannon entropies. evidence is presented that identical or closely related consensus sequences may hide different subpopulations of genomes bearing distinct relationships among them. the origin of bhk- cells, and procedures for cell growth, and infection of cell monolayers with foot-andmouth disease virus (fmdv) have been previously described [ ] [ ] [ ] , ] . the following fmdv clonal populations have been used in the studies on lethal mutagenesis: i) fmdv c-s c , a plaque-purified derivative of the natural isolate c santa-pau spain [ ] , a representative of european serotype c fmdv [ ] , genbank accession number nc_ ; ii) c-s c multiply passaged at high multiplicity of infection (m.o.i.) in bhk- cells; the viral populations derived from each passage are indicated with a "p" before the passage number (i.e. c-s p means c-s c passaged times in bhk- cells). iii) fmdv marls, a monoclonal antibody (mab)-escape mutant, selected from population c-s c p [ ] , genebank accession number af . iv) c-s c p p d, the viral population resulting from three diluted serial infections (mo.i. = . ) of c-s c p in bhk- cells [ ] ; gene bank accession number dq ; v) c , a clone derived from subjecting c-s c to plaque-toplaque transfers in bhk- cells [ , ] . procedures for extraction of rna from the supernatants of infected cell cultures, reverse transcription (rt) of fmdv rna and pcr amplification with high fidelity pfu dna polymerase have been previously described [ , , , ] . molecular cloning in plasmids pet- a dpol or pmt- , as well as controls to ensure that molecular clones reflect accurately the composition of the quasispecies under analysis, were described in the primary publications that produced the genomic sequences analyzed here [ , [ ] [ ] [ ] [ ] . nucleotide sequencing was performed using the big dye terminator cycle sequencing kit (abi prism; applied biosystems) and the automated sequencer abi and abi ; all sequences were determined at least in duplicate, from independent sequencing reactions. the procedures used for the mutagenic treatment have been described in detail in the primary references [ , , [ ] [ ] [ ] . here we provide a summary. a mm solution of r (kindly provided by jc de la torre) was prepared in pbs, sterilized by filtration, and stored at - °c. prior to use, the stock solution was diluted in dmem (dulbecco's modification of eagle's medium) to reach the desired working concentrations (generally μm to μm). cell monolayers were preincubated with r for h prior to infection. infections in the absence of r, and mock-infected cells were maintained in parallel. fmdv marls was serially passaged in the presence and absence of increasing concentrations ( μm to μm) of r ( figure. ). for each passage, × bhk- cells were infected with - × pfu of virus from the previous passage until cytopathology was complete (about h in the presence of r, and h in the absence of r) [ , ] . treatment with fluorouracil, azacytidine and guanidine hydrochloride -fluorouracil (fu) and azacytidine (azc) were used as mutagenic base analogues (figure ), while guanidine hydrochloride (g) was used as inhibitor of fmdv replication, as previously described [ , , ] . fu medium contained μg/ml fu, and fug medium contained μg/ml fu and mm g. solutions were sterilized by filtration and stored at °c for a maximum of days before use. infections in the presence of fug were performed as previously described [ , , ] . the sources of all reagents for molecular studies are given in the corresponding references that describe the nucleotide sequences used in the present analyses [ , , , ] . multiple alignments of consensus sequences and molecular clones were carried out with the program clustal w [ ] , inserted into bioedit package [ ] , using fmdv c-s c and/or fmdv marls (genbank accession numbers aj and af , respectively) as the reference sequences. pairwise distances matrix was generated by the program mega . [ ] , using the kimura- parameter model [ ] . tree topology was inferred by three phylogenetic methods: (i) neighbor-joining (nj) [ ] using also the mega . package [ ] ; bootstrap re-sampling ( data sets) of the multiple alignments was used to test the statistical robustness of the trees obtained by nj [ ] . (ii) maximum parsimony (mp) (using the program dna-pars from phylip v . package) [ ] . (iii) maximum likelihood (ml) trees were generated by the program puzzle [ ] using the tamura-nei substitution model [ ] , and the gamma distributed rates with eight parameters (tn- Γ) as heterogeneity model (see additional file ). additionally, for the additional file , a ml analysis of mutagenized populations of fmdv was performed by means of the program modelgenerator [ ] , useful to identify the optimal evolutionary model (akaike information criteria and hierarchical likelihood ratio test indicated that the gtr model best fit the sequence data). using this model, ml trees were constructed using software from the phyml program [ ] , available at [ ] . as a measure of the robustness of each node, we used an approximate likelihood ratio test (alrt), which assesses that the branch being studied provides a significant likeli- a) the initial biological clone c-s c [ ] was subjected to three parallel series of cytolytic infections, either in the presence of -fluorouracil (fu) or -azacytidine (azc) or with no drug. b) c-s c was subjected to passages, and then marls clone was isolated as a mab sd resistant mutant [ ] (thin arrow). ra populations originated from serial cytolytic infections of marls in the presence of the indicated concentrations of ribavirin (r). the concentration of r was increased from μm to μm in the first passages and from μm to μm between passages and . a bifurcation was established at passage and the populations were subjected to additional passages in the absence of r to yield the population ra p . cap is the population obtained after parallel passages of marls in the absence of drug. hood gain, in comparison with the null hypothesis that involves collapsing the branch under study but leaving the rest of the tree topology unaffected [ ] . the complexity of mutant spectra was quantified by minimum and maximum mutation frequencies. minimum mutation frequency is the number of different mutations present in the molecular clones divided by the total number of nucleotides sequenced, and maximum mutation frequency is expressed as the total number of mutations present in the molecular clones divided by the total number of nucleotides sequenced. the normalized shannon entropy (h), which is a measure of the proportion of identical sequences in a distribution [ ] , was also calculated. it is given by the formula: in which p i is the proportion of each sequence of the mutant spectrum, and n is the total number of sequences compared. for the partition analysis of quasispecies (paq) [ ] , the clones of each viral population were grouped together under the minimum possible radius, considering no partition. within each cluster, the average distance (ad) value, with respect to the central sequence reported by paq, was calculated as a measure of the intrapopulation diversity, given by the formula: in which n is the number of neighbors within the group with centre variant c, and d ic is the genetic distance (hamming) between variants i and c. the populations are represented as spheres with the diameter proportional to the ad value. standard errors have also been calculated (see additional file : standard errors). the nonsynonymous mutations corrected per nonsynonymous site (dn) and the synonymous mutations corrected per synonymous site (ds) were calculated using snap [ , ] . kn and ks are the ratio of nonsynonymous and synonymous mutations respectively, per nucleotide (without any correction). the sliding-window software k-estimator [ ] was used to infer the ks and kn in the fmdv genome using nucleotide windows and a shift of nucleotides per step, to cover all the polyproteincoding region. the software calculates the confidence interval using monte carlo simulations. software for phylogenetic and sequence analyses were retrieved from the corresponding references listed in the different sections of methods. one way anova, tukey post hoc tests for non equal n, and standard errors were calculated using statistica . software package (statsoft ). the present study was aimed at analyzing retrospectively sets of consensus and clonal nucleotide sequences determined in our laboratory from fmdv populations subjected to serial cytolytic infections in bhk- cells, in the absence or presence of the mutagenic nucleotide analogues fu, r or azc [ , , , ] -( figure ). a representation of the quasispecies was obtained by determining the nucleotide sequences of to cdna clones from each population, and scoring mutation types, mutation frequencies, and shannon entropies. the fmdv genomic region analyzed was the d (polymerase)-coding region (table ) . phylogenetic trees were derived from the nucleotide clonal and consensus sequences from each population. sequences from some reference viruses were also introduced as outgroups to establish minimal and previously known relationships, as well as to define a general structure of the tree. the distance-based nj method [ ] , under kimura two parameter model [ ] , was initially used for phylogenetic reconstructions, as described in methods. in some cases the populations were analyzed using ml and mp algorithms [ ] (see additional files and ). the general topology of these trees was consistent with that derived from the nj analysis: the major clades and the relationships among clonal and consensus sequences were maintained. comparison of the phylogenetic trees derived from nucleotide sequences of the different fmdv clonal populations passaged and times in the absence or the presence of azc or fu shows an expansion of genetic distances among components of the mutant spectrum of the mutated populations compared to the respective control populations passaged in the absence of drug. the presence of fu led to a higher expansion of the genetic distances than the presence of azc ( figure ). this expansion was not observed at passage either with or without azc or fu. tree branches radiate from the corresponding consensus sequence with no discernible subclusters within each population. a more complex pattern of intrapopulation genetic distances was observed with fmdv passaged in the presence of r (figure ). these populations originated from the high fitness fmdv clone marls [ ] . the overall topology of the populations subjected to continuous mutagenic treatment (rap , rap and rap ; passage history depicted in figure ) shows the absence of significant subclusters. in turn, in all cases, a set of clones centrifugally diverge from the consensus sequence located at the basis of the group. as the number of passages in the presence of r increases, the genetic distance between the consensus sequence of each population and its parental marls clone increases substantially (about -fold from passage to passage ; figure a ). interestingly, the population that underwent passages in the presence of r and then passages in the absence of r, showed a more compact topology, and subclusters of clones were distinguished (ra p * in figure b ). it must be noted that, due to the close relatedness among the nucleotide sequences analyzed (see background and methods), the bootstrap values associated with the derived nj trees suggest limited robustness of the derived clusterings. nevertheless, the same general topological features are also observed when mp and ml were used (see additional file : neighbour-joining, maximum likelihood and maximum parsimony analysis of populations rap and ra p ) (see also statistical evaluation of paq, below). the control population cap , obtained after serial cytolytic infections of clone marls in cell culture in the absence of mutagen, shows a characteristic tree with evident lower diversity than the populations treated with mutagen ( figure ), as documented by the very low mutation frequency value ( -fold smaller than population rap , see table ), and the average shortness of all the branches. to further characterize the clonal structure of mutagenized fmdv populations, paq was applied to the same fmdv populations (figure ) studied by phylogeny. the sequences determined from the set of molecular clones derived from each viral population were treated as separate populations. a radius that grouped all sequences was chosen, and then the ad value was calculated (see methods), as a measure of intrapopulation diversity ( figure ) . we considered the absence of intrapopulation partition as a priori realistic assumption because each viral population derives from a well defined ancestor and evolution took place under controlled conditions, supported also by phylogenetic data ( figure a ). a the origin of the fmdv populations is detailed in methods and depicted schematically in figure . b the genomic residues analyzed correspond to the d-coding region of the fmdv genome; residue numbering is according to [ ] . c drug treatment (azc, azacytidine; fu, -fluorouracil; r, ribavirin), and concentrations are as described in figure . d the first number indicates the total amount of different mutations found in all the clones analyzed; when repeated mutations were found the second number refers to the total number of mutations. e expressed per in each population. f minimum mutation frequency is the number of different mutations divided by the total number of nucleotides sequenced. g maximum mutation frequency is the total number of mutations (including repeated mutations) divided by the total number of nucleotides sequenced. h h is the normalized shannon entropy [ ] . i ad is the average genetic distance, calculated as detailed in methods. the value in brackets was calculated with residues - (to compare with population ra p ) of the fmdv genome. a dramatic effect of r treatment was unveiled by paq through the comparison of marls populations passaged in the presence or absence of r ( figure b) . . ) than the population cap , the parallel control in the absence of the drug ( figure b ). the d of rap and its derived populations harbours the substitution m i which decreases its sensitivity to r [ ] . further passages in the presence of μm r led to a reduction of diversity of population rap ( . -fold reduction in ad value, tukey post hoc test, p < . ; table ). once the diversity decreased in rap , it did not further increase significantly after additional passages under higher (up to μm) concentrations of r (rap ) ( . fold, tukey post hoc test, p = . ). population rap (depicted in figure b ) was subjected in parallel to further passages either in the absence (ra p ) or the presence (rap ) of r. the intrapopula-tion diversity in ra p was . -fold smaller than rap (tukey post hoc test, p < . ) (see discussion). the modification of the relationship among components of the mutant spectrum is not reflected in shannon entropy (which is saturated in the highest value, , for all the populations from the ra lineage tested) (see table ). also maximum mutation frequency varies within a narrow range of . -fold to . -fold when the different populations are compared with rap (table ) . there are no statistically significant differences in the minimum/maximum mutation frequency of population rap and ra p (one-way anova: f = . , df = . , p = . ). this ratio is larger (higher diversity) in populations rap and rap , than in population rap (tukey post-hoc test, p = . and p = . , respectively), despite having lower ad values and, therefore lower intrapartition analysis of quasispecies (paq) applied to sequences derived from mutagenized fmdv populations figure partition analysis of quasispecies (paq) applied to sequences derived from mutagenized fmdv populations. the initial biological clone of each passage series is depicted as a dot, with an initial intrapopulation average distance given arbitrarily the value ad = . . the populations analyzed in a and b are those described in figure a and figure b , respectively. for simplicity, only the drug treatment (fu, -fluorouracil, green; azc, azacytidine, blue; r, ribavirin, black; no drug, red), and the populations analyzed are depicted. the ad value was measured for each population considering no partition. values are based on nucleotide sequences of the d(polymerase)-coding region, genomic residues to for a), and to for b), except for population ra p for which residues - were used. for comparison, population rap was also analyzed using residues - ; in that case the sphere is represented with a dotted line inside the large sphere. the diameter of each sphere is proportional to the ad value which is indicated next to each sphere. procedures for nucleotide sequencing and paq analysis are described in methods. population diversity. these comparisons support that the ad values derived from paq are a more sensitive and realistic descriptor of intrapopulation diversity than mutation frequencies. the mutation profile in the components of the mutant spectrum of each population analyzed indicated that a specific pattern of mutations was associated with each mutagen ( figure ). fu-treated populations accumulated an excess of u → c transitions [ ] , while -ra popula-tions preferentially fixed transitions c → u and g → a [ ] . the mutational bias associated with azc was mainly due to transversions g → c, c → g. the nj tree derived from consensus nucleotide sequences of the entire fmdv genome of r treated populations disclosed an unusually rapid fixation of mutations in the consensus sequence of rap ( figure a ). in the course of serial cytolytic passages of c-s c , mutations accumulated at a rate of approximately . mutations per passage [ ] , with marls displaying a similar rate of . proportion of the different mutation types scored among molecular clones of fmdv populations quantification of the genotypic divergence of fmdv marls populations passaged in the presence of ribavirin the fmdv populations analyzed are those derived from c-s c or marls, as displayed in figure b . a) phylogenetic tree based on consensus nucleotide sequences of populations derived from biological clone c-s c (p , p , p , p ) and from marls (rap , rap ); p p d derives from c-s c after passages at high m.o.i. in bhk- cells, followed by low m.o.i. infections, as described in [ ] . c a is a clone of c-s c subjected to serial bottleneck (plaque-to-plaque) transfers in bhk- cells [ , ] . fmdv c-oberbayern is a natural isolate whose sequence [ ] has been used as outgroup. the tree is based on the nucleotide sequence of entire genomes, using the nj method with bootstrap resamplings (nodes scoring values higher than per are indicated in the tree), following the procedures described in methods. b) absolute number of mutations including reversions, relative to the sequence of c-s c , as a function of passage number in the c-s c lineage (depicted in figure b ). values are based on the nucleotide sequence of entire genomes. a linear regression constructed with c-s c and successive passages (c-s c lineage) is shown (y = . x- . ; r = . ). the position of marls and rap is indicated. procedures are detailed in methods. mutations per passage. in contrast, ra deviated to . mutations per passage, suggesting a very fast evolution associated with the presence of r ( figure b ). we have examined whether the highly mutated ra genomes resulted from random fixation of mutations along the genome, or from their preferential accumulation at specific genomic sites. using the sliding-windowbased software k-estimator [ ] (described in methods) we measured the distribution of mutations (ka, ks, nonsynonymous and synonymous mutations per nucleotide, respectively) along the open-reading frame (polyproteincoding region) of marls, rap and rap populations. at certain genome regions, ka and ks for rap and rap displayed values that were statistically significantly higher than the average (figure ) . the asymmetric distribution of mutations suggests that despite the high mutational pressure imposed by r treatment, some kind of selection is still acting during the -passaging of the virus with error-prone replication. to distinguish whether the asymmetric distribution of mutations along the genome was mainly due to positive or negative (or purifying) selection, the dn/ds ratios were calculated (see methods and table ). -ra populations included -to -fold excess of synonymous mutations, both in the analysis of the mutant spectrum and the consensus sequence. in contrast, the dn/ds ratio of the consensus sequence of c-s c at passage (c-s p p d) was . , that is, -to -fold higher than the value for -ra populations. also, a set of marls-derived clones scored a dn/ds ratio of . , -to -fold higher value than obtained in the clonal analysis of -ra populations ( table ) . these data, together with the non-random accumulation of mutations along the viral genome (figure ) , strongly suggest that purifying selection operates on fmdv in the course of replication under enhanced mutagenesis. to investigate whether fmdv extinction by enhanced mutagenesis was associated with unusual intrapopulation divergence [ , , , ] , a paq analysis was performed on populations fmdv c-s p , c-s p -fug and rap [ ] (figure a) . preextinction population c-s p -fug manifested a very modest increase in mutant spectrum complexity relative to the control population c-s p (figure c) . furthermore, the complexity of c-s p -fug was much lower than the complexity of rap (ad value comparison: t student, t = . , p < . ), included in the phylogenetic and paq analyses ( figure b and c) . therefore, viral extinction can be achieved without any salient increase of the average genetic distances among components of the quasispecies (see discussion). several remarkable modifications in the mutant spectrum occur when viral populations replicate in the presence of mutagenic agents such as base or nucleoside analogues. the initial experiments by j.j. holland and colleagues documented very modest ( . -to . -fold) increases of mutation frequency at single base sites of poliovirus and vesicular stomatitis virus, associated with severe decrease of infectivity, as a consequence of enhanced mutagenesis by a variety of mutagenic agents [ ] . subsequent work showed that replication of different viruses in the presence of mutagenic base or nucleoside analogues could lead to virus extinction accompanied of very modest (from barely measurable up to . -fold) increases of mutation frequency and mutant spectrum complexity ( [ , , ] ; reviews in [ , , ] ). in our previous studies with fmdv and lymphocytic choriomeningitis virus we have observed that in the course of the transition of the viruses towards extinction: i) there is a -to -fold decrease in specific infectivity (number n.d. not determined. a the viral populations analyzed are those described in figure and methods. b dn/ds is the ratio of nonsynonymous mutations (corrected per nonsynonymous site) to synonymous mutation (corrected per synonymous site), calculated as described in methods [ , ] . values correspond to calculations using nucleotide sequences from molecular clones (as described in table ). c dn/ds calculated as in b, applied to consensus nucleotide sequences, compared with the corresponding parental clone (given in parenthesis). d this value was calculated with biological clones derived from marls, using the l (leader) protease-and capsid-coding regions. distribution of ka and ks ratio (non-synonymous mutations per nucleotide, and synonymous mutations per nucleotide, respec-tively) along the consensus sequence of the protein-coding region of the genomes of fmdv marls, rap and rap figure b . the sequences have been compared with that of c-s c . ka and ks were calculated with the software k-estimator [ ] . the genomes were analyzed in windows of nt and a shift of the window of nt in each step. the scaled protein-coding region of the fmdv genome is indicated in the abscissa [ , ] . the confidence intervals (dotted horizontal line) were calculated by k-estimator using monte carlo simulations [ ] . a) ka ratios. b) ks ratios. c) comparison of ka and ks ratios for rap . preextinction fmdv population, and phylogenetic and paq analysis of mutagenized populations the tree includes also clones derived from the population obtained after passages of c-s c in the presence of fu and g (green asterisks), or in the absence of drugs (red dots). the central sequence according to paq is indicated by an arrow. populations p , p p d and clone c , are derived from c-s c , as described in figure . the tree is based on residues to of the d (polymerase)-coding region, using the neighbor-joining method ( bootstrap resamplings; values higher than are indicated with numbers; values between and are indicated in parenthesis), as detailed in figure and methods. c) ad values and spheres corresponding to the paq analysis of populations rap , c-s p -fug and c-s p . procedures are detailed in methods. of infectious units divided by the total amount of viral rna); ii) low viral loads and low replication capacity (fitness) favour extinction; and iii) internal, interfering interactions among mutagenized components of the mutant spectra play an important role in the extinction [ ] [ ] [ ] [ ] [ ] , , ] . the critical participation of the mutant spectrum in viral extinction led to the proposal of "lethal defection" as a model of virus extinction by lethal mutagenesis [ , ] , and motivated the phylogenetic and partition analyses of mutant spectra reported in the present study. the results support our previous conclusions on the general increase of mutant spectrum complexity -here documented by average genetic distances in phylogenetic trees and quantified by the ad parameter in paq-as a result of the various mutagenic treatments. moreover, new insights into the events associated with enhanced mutagenesis have been unveiled by the comparison of phylogenetic and paq analyses. the nj tree topology of a population evolved under enhanced mutagenesis conditions consists of a basal consensus sequence, with the individual components of the population radiating from it (the more mutated the population the bigger the radiation of the branches) and with no apparent population structure in the form of subclusters. trees constructed with fmdv populations whose d (polymerase) included a substitution that decreased the sensitivity to r (rap and rap ) [ ] displayed a slight reduction of branch length, but maintained the same general topology. this is in sharp contrast with population ra p , which, after only passages in the absence of r, presents an internal structure completely rearranged, as shown by the nj tree, and confirmed with ml and mp methods ( figure b , and additional file : neighbour-joining, maximum likelihood and maximum parsimony analysis of populations rap and ra p ). the average distance parameter ad of paq reflects the fine detail of the intra population structure of diversity better than the other estimators traditionally used, such as mutation frequencies or shannon entropy. mutation frequency does not capture the distribution of mutations among the individual components of a mutant spectrum, and the shannon entropy reaches the maximum possible value of when all the sequences under study are different, independently of the mutational load. this lack of resolution is circumvented by paq due to the pairwise comparison of all the clones with respect to the central sequence. in this sense, any subtle variation in the spatial distribution of mutation frequency may be amplified yielding a more sensitive, accurate and non-saturating description of the internal structure of the population. the present analysis has documented striking expansions of the average intrapopulation genetic distance associ-ated with mutagenic treatments (figure ) . interestingly the analysis of the ra lineage revealed that, after an initial expansion of intrapopulation diversity, a remarkably fast contraction of the average distance occurred in two situations. first, a . -fold reduction in ad value was observed when the drug treatment was discontinued for only passages. second, populations with fmdv including in its d (polymerase) replacement m i -that decreases the sensitivity to r [ ] -displayed a . -fold reduction in ad value (rap and rap populations, figure ). the ratio of minimum over maximum mutation frequency yielded higher values (indicative of higher diversity), in populations rap and rap than in population rap which is the most diverse. therefore mutation frequencies (both maximum, minimum or their ratio) and shannon entropy, are less definitory than paq (when analyzing ad) to characterize the internal genetic diversity of mutagenized viral populations. a possible interpretation of intrapopulation contractions is that in the course of the mutagenic treatment subsets of genomes with better than average replication efficiency are produced. however, their potential replicative advantage can not be expressed due to the continuous mutational input due to the presence of r. when r pressure is removed, specific subsets of genomes showing higher than average replication capacity, replenish the population. a similar, albeit less pronounced, contraction would occur as a consequence of the dominance of viral mutants with decreased sensitivity to r. the marls-derived populations that replicated in the presence of r (the ra lineage, figure b) , showed unexpected high resistance to extinction at passage and subsequent passages, associated with a mutation that decreased the sensitivity to r [ ] . despite such mutation, the number of total mutations fixed in the consensus sequence of population rap was very high ( . mutations/passage, figure ) when compared with its ancestor ( . mutation/passage). also the molecular clones derived from rap presented a -fold increase in mutation frequency with respect to the control population, cap (table ). the specific pattern of mutations of fu-treated, azc-treated and r-treated populations ( figure ), and the increase in mutant frequency with respect control populations (table ) suggest that the increase in mutation frequencies was effectively produced by the action of mutagens, in agreement with the mutational bias induced in the course of polymerization assays in the presence of r-triphosphate or fu-triphosphate using purified fmdv d (polymerase) ( [ ] , agudo et al submitted for publication). despite the high error frequencies induced by mutagen, mutations did not accumulate at random along the viral genome, but rather they accumulated at preferred genomic regions (figure ) . the non-random accumulation of mutations and the excess of corrected synonymous mutations (table ) are consistent with purifying selection operating in the evolution of mutagenized populations. viruses harbouring less deleterious mutations might have a selective advantage in a landscape of highly damaged viruses. in this view, the quasispecies would display a mutagenesis buffering activity, accepting those mutations that affect the more permissive regions of the viral genome. this dynamics is strikingly parallel to that observed in the course of bottleneck transfers carried out with the same fmdv clones c-s c ( [ , , [ ] [ ] [ ] reviewed in [ ] ). in bottleneck transfers individual clones are selected for replication. in this situation müller ratchet effect operates on the clones [ ] . in clones that resisted extinction, mutations accumulated preferentially at some genomic regions and, again, an excess of synonymous mutations was found [ , ] . the present study supports the "lethal defection" model of viral extinction in that a limited number of mutations per genome can be sufficient to drive a virus to extinction [ , , ] . again, the comparison with fmdv clones subjected up to bottleneck transfers is highly significant. in such clones extinction was not achieved despite the genomes reaching average mutation frequencies which are -to -fold higher than those associated with viral extinction by lethal mutagenesis [ , , , ] . it has been proposed that in successive bottleneck transfers, the kinetics of mutation accumulation allows the fixation of compensatory beneficial mutations that counteract the müller ratchet effect [ ] [ ] [ ] [ ] . several theoretical models of lethal mutagenesis of viruses have been proposed, either as a direct consequence of quasispecies dynamics and its corollary concept of error catastrophe, or independently of error catastrophe [ , [ ] [ ] [ ] [ ] . all models converge in that lethal mutagenesis is a feasible strategy to achieve virus extinction by mutagenic nucleotide analogues. what the models did not take into consideration is the key influence on extinction of internal interactions exerted among components of the mutant spectra. lethal and interfering mutations impede a substantial "evaporation" (or "diffusion") of genomic sequences in sequence space [ ] , as it could not be otherwise, considering that we are dealing with loss of multiple biological functions compactly integrated in a viral genome [ ] . the phylogenetic and paq approaches used here should be extremely helpful to monitor in a quantitative fashion the evolution of mutagenized viral populations both in cell culture and in vivo, as they increase their mutational load and either succumb or escape extinction. phylogenetic and paq analyses have unveiled changes in the internal population structure of fmdv viral quasispecies subjected to mutagenesis by base and nucleoside analogues. expansions and compressions of mutant spectra have been quantitated by comparing average genetic distances among components of mutant spectra. comparisons of the types and distribution of mutations along the viral genomes have shown that negative (or purifying selection) acts in the course of enhanced mutagenesis. virus extinction can be achieved with modest increases of population complexity. the average distance parameter (ad) reflects the intrapopulation structure better than the other 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implications for viral extinction structure of foot-and-mouth disease virus rnadependent rna polymerase and its complex with a template-primer rna mutant viral polymerase in the transition of virus to error catastrophe identifies a critical site for rna binding genomic nucleotide sequence of a foot-and-mouth disease virus clone and its persistent derivatives. implications for the evolution of viral quasispecies during a persistent infection molecular cloning: a laboratory manual curing of foot-and-mouth disease virus from persistently infected cells by ribavirin involves enhanced mutagenesis clustal w: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice bioedit: a user-friendly biological sequence alignment editor and analysis program for windows / /nt mega : integrated software for molecular evolutionary genetics analysis and sequence alignment a simple method for estimating 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antiviral strategy quasispecies, error catastrophe, and the antiviral activity of ribavirin production of guanidine-resistant anddependent poliovirus mutants from cloned cdna: mutations in polypeptide c are directly responsible for altered guanidine sensitivity mutation frequencies at defined single codon sites in vesicular stomatitis virus and poliovirus can be increased only slightly by chemical mutagenesis combination of a mutagenic agent with a reverse transcriptase inhibitor results in systematic inhibition of hiv- infection molecular indetermination in the transition to error catastrophe: systematic elimination of lymphocytic choriomeningitis virus through mutagenesis does not correlate linearly with large increases in mutant spectrum complexity high mutation rates, bottlenecks, and robustness of rna viral quasispecies resistance to extinction of low fitness virus subjected to plaque-to-plaque transfers: diversification by mutation clustering multiple molecular pathways for fitness recovery of an rna virus debilitated by operation of muller's ratchet population bottlenecks in quasispecies dynamics the relation of recombination to mutational advance the error threshold theory of lethal mutagenesis for viruses lethal mutagenesis early replication: origin and evolution simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions comptutational analysis of hiv molecular sequences the authors wish to thank o.gordo for critical review of the manuscript, and c escarmís for important contributions to this project. work at centro de biología molecular "severo ochoa" was supported by grants bfu - from mec, / from fipse, and fundación r.areces. work at centro de astrobiología was supported by inta, mec, cam and ue. ciberehd is funded by instituto de salud carlos iii. s.o. was supported by a predoctoral fellowship from the ministerio de educacion y ciencia. ra, ms, ss and cg-l determined nucleotide sequences. so, cb and jc applied phylogenetic and paq methods. so made the calculations. ed conceived the study, and so and ed wrote the manuscript. all authors reviewed and approved the final manuscript. neighbour-joining, maximum likelihood and maximum parsimony analysis of populations rap and ra p . strains in the tree are shown by name. consensus sequence of each population is indicated with an asterisk. bar at the bottom of the trees denote distance a) and d) neighbour joining trees with key: cord- -b xuzkbb authors: fal’tsman, v. k. title: on urgent socioeconomic measures during the corona crisis date: - - journal: stud russ econ dev doi: . /s sha: doc_id: cord_uid: b xuzkbb in anticipation of the impending crisis, the article considers two branches of anticrisis measures: ) the creation of an economic structure that ensures the accelerated growth of small and medium-sized enterprises, the products of which can partially offset the loss of income from the export of hydrocarbons due to import substitution and export of manufacturing goods and services; ) social protection of the poorest segments of the population from the possible increase in unemployment and poverty. an emergency has occurred in the russian economy [ ] [ ] [ ] [ ] . in the past five years, the country has been close to zero growth. competition in the hydrocarbon market is intensifying, and the most affordable oil reserves are poorer. in conditions of budgetary dependence on oil and natural gas, world prices for oil and natural gas are falling. sanctions are constantly growing. due to the complicated geopolitical situation, the russian economy carries an increased external load. dangerous competition with chinese producers is intensifying. due to depopulation, the number of people employed in the economy is declining. the cadres are getting old. the covid- pandemic added unprecedented unpredictability to the situation. the pandemic hit hard on business, especially passenger transportation, tourism, and catering. the magnitude of the impending destructive impact of the pandemic on the global and russian economies has not yet been determined. but global oil demand has already fallen by %. we will arbitrarily denote the future crisis as a "corona crisis." regardless of the timing and extent of the emerging economic crisis, a number of urgent stabilization measures are needed to contain its effects. among the most important of them, in our opinion, is a deep institutional reform of the economy, aimed at creating a special economic structure for the accelerated development of small and medium-sized enterprises (smes). world experience shows that this is the first, if not the only, way out of the russian economy from the zone of zero growth. for example, in the united states, % of the million operating companies are smes. in russia, the situation is different: smes are under heavy pressure from the state administration, corruption, and large enterprises. the development of production at sme enterprises should be aimed at compensating for possible losses from the reduction in sales of oil, natural gas and other traditional goods and services of the russian economy. but in an emergency, most likely, it will not be possible to avoid a corona crisis. therefore, the second part of the article discusses some areas of social support for the population from the threatening consequences of the crisis. on the formation of a special economic structure for the accelerated development of smes. for the formation of a second economic structure of the russian economy, it is not enough to limit oneself to traditional methods of supporting the development of smes, let alone their surface imitation. we need a deep institutional reform of the still weak sphere of smes [ ] . the essence of the reform is to create conditions for the use of local entrepreneurial initiative, local resources and markets for the development of domestic goods production, import substitution and nonresource exports. to this end, the local entrepreneurial initiative must be exempted from the custody of the registering, licensing, inspection bodies, whose activities are sometimes associated with corruption. smes are capable of producing a rich harvest of income and taxes in a short time. but you should not start harvesting when the cornfield has not yet ripened. taxes (along with corruption and criminality) are the most dangerous enemy of smes, while they are not adequately protected by local and regional authorities. an ill-conceived fiscal policy can stifle weak sprouts of smes in the bud. for the success of the business, it may be advisable for a limited period to completely exempt new products from small enterprises from taxation. in any case, preferential taxation should be the primary measure of the upcoming reform of sme development. the accelerated development of smes implies increased decentralization of economic development management. responsibility for accelerated growth in the turnover of smes should be assigned to the regional and local administration, for which the main indicators of the quality of work should be indicators of the development of smes. under this condition, the regional and local authorities will be forced to facilitate the access of smes to land, water, energy and transport infrastructure, and access to local markets without pretending to corrupt rents. the tax code and other regulatory documents should provide for the strengthening of the economies of regions and municipalities through the development of smes, a gradual reduction in centralized subsidies. the formation of a second economic structure through institutional reform is exclusively constructive in nature, and can be aimed at strengthening the powerful vertically integrated system of large enterprises belonging to the first economic structure. with the support of the federal government, the regional entrepreneurial sector is able to complement and reinforce the powerful public sector, which forms the basis of the russian economy and includes defense industry enterprises, the fuel and energy complex, transport, financial and other organizations. the economic structure of the sme sector not only does not suppress large state enterprises, but is also able to strengthen their economy. for example, smes can help solve the complex problem of diversification of defense industry production into civilian products. but for this, the federal government should facilitate the joint activities of smes with defense industry enterprises, which is currently limited by the conditions of secrecy. sme enterprises, somewhere on their own, and somewhere together with foreign companies, can help localize the production of cars by replacing the import of components and accessories, the scale of which in some years reaches - billion dollars. most russian industries (except the extractive and financial sectors) have little chance of winning competition for international capital in global financial markets. as the corona crisis unfolds, capital outflows will increase. therefore, after the successful strengthening of smes (but not earlier!), it can become an internal source of investment for large enterprises in the public sector. labor productivity in small enterprises is . times higher than in the national economy as a whole. however, small businesses, with the exception of startups, have limited opportunities for the development and production of innovative products. moreover, the pre-dominant number of smes is concentrated in industries with a relatively low high technology output -in construction, agriculture, trade, and repair of household appliances. the proportion of innovative products in small enterprises is half that of medium-sized enterprises, and five times less than in the national economy as a whole. however, the potential contribution of smes to the innovation process, we believe, is to expand the possibilities of implementing local creative initiatives and preserving domestic human capital from diversion abroad. the level of innovative activity and competitiveness of smes can be increased by creating and distributing state-owned enterprises leasing foreign equipment. at the first stage of radical institutional reform, perhaps one should confine oneself to the accelerated growth of smes in the production of consumer goods including food, clothing, footwear and the necessary agricultural and chemical raw materials, as well as household appliances. these are areas with wide opportunities for import substitution and accelerated capital turnover. promising areas for the development of smes are also individual housing construction, local tourism, and startups. financing the accelerated development of smes should be based mainly on the private capital of owners with moderate and limited loans from regional and municipal sources. it was this way that the development of silicon valley startups went. loans at the federal level can pose a threat to smes: financial support from the state will inevitably be followed by inspections and strengthened government regulation, which is detrimental to private initiative. meanwhile, in the last years of the recession and the worsening economic situation, the autonomy ratio of small enterprises has halved: three quarters of their capital is borrowed. in these conditions, the threat of curtailing the activities of smes under the influence of the crisis is great. therefore, to maintain the growth of the russian economy, a deep institutional reform is needed that promotes the economic structure of the accelerated development of smes. in the economic life of russia, this reform is called upon to play about the same role as the development of oil and gas production and export in the - s. social protection of the population from the corona crisis. according to world ratings, russia is not a poor country. in terms of gdp (ppp) per capita, the country is in th place in the world. but in terms of relative poverty, the country adjoins a group of countries with low rates. the reason for the discrepancy between income and poverty levels is a high income differentiation, which exceeds (by the ratio of extreme decile groups) times. in the favorable period - , the proportion of the population with incomes below the subsistence level decreased from . to . %. but in subsequent years of the recession, the propor-tion of the poor began to grow. meanwhile, in the country there are dollar millionaires [ ] . in the years of the upcoming crisis, the challenge is to limit the spread of poverty, to prevent it from developing into a stage of poverty, when the state of the economy begins to adversely affect the health of the population and reduce the outlined increase in the active longevity of people. in the context of the corona crisis, the most important measure of social support for the population from its consequences, in our opinion, is the redistribution of part of the income from the richest to the poorest. the prerequisites for such a redistribution of income have been formed over the past years, when russia's per capita gdp (ppp) grew by about three times. accordingly, incomes and well-being of the wealthy segments of the population, their provision with equipment, real estate and other goods with the possibility of deferred demand increased. now the need has ripened for highly profitable groups of the population to introduce a progressive taxation scale adopted in many countries of the world. for the poorest segments of the population, taxes can be reduced, or, without canceling personal income tax, introduce targeted support for low-income families. in this latter case, support is financed by federal and regional budgets from funds from raising taxation of high incomes, and is implemented by local authorities, municipalities and prefectures. in the second quarter in , the proportion of the population with cash income below the subsistence level was . %. this is . million poor people. to bring the incomes of this poor group to a living wage, according to rosstat estimates, they will need to add an additional amount equal to . % of the total income of the population. in order to completely get rid of poverty, it will take only about billion rubles. in anticipation of the impending crisis, russia was one step away from the opportunity to get rid of poverty. true, from nominal poverty and calculated by the russian method, different from european. how will the structure of income distribution change if, by introducing a progressive taxation scale, this amount is removed from high-income segments of the population and redistributed in favor of the least wealthy? rosstat shows the distribution of the total cash income of the population into five groups. in each group is equally % of the population, about million people. but the volume of cash income by group is very different. if we take the total income as %, then the fifth group with the highest incomes accounts for . % of revenues, the next fourth group, . %, and the total for two highly profitable groups, . % of income. if the amount equal to . % of total income is withdrawn from these two groups through tax reform, then their share in the total amount of cash income will decrease slightly to . %. but at the same time, the share of the first group with the lowest incomes, which includes . million poor people, will increase from . to . %. from the introduction of a progressive taxation scale, affluent groups of the population will suffer slightly, and the most needy segments of the population will no longer be considered poor. the progressive scale of taxation of the rich may prove to be an indispensable measure of social protection of the population from falling incomes during the corona crisis. the magnitude and duration of the crisis is currently unpredictable. therefore, there is nothing left but an analysis of hypothetical assumptions. suppose the worst (according to modern estimates) scenario, when the level of per capita gdp (ppp) and, accordingly, population incomes will be reduced by a third. then the size of the country's economy and standard of living will be reduced by the crisis to the level of about ten years ago, in - . if the resulting losses are evenly distributed among all population groups, poverty will inevitably spread, and for the poorest segments of the population it will grow into poverty. therefore, for the first three groups of the less welloff population, it is desirable to keep the income at the same level and load the entire severity of the crisis on the remaining two groups of the richest people, fairly distributing the loss of income in accordance with the progressive taxation scale. as we have already said, the two groups of the population with the highest incomes account for about % of the total cash income of the population. the hypothetical reduction of the total income by one third will make the wealthy people of these groups almost twice as poor. how vulnerable are these two groups to such a loss of income? according to the federal state statistics service, households spend on the purchase of nonfood products (cars, yachts, other home appliances, real estate, etc.) in the fifth highest-income group of the population, . % of their income, and in the previous fourth group, . % of income. the acquisition of these goods with the properties of deferred demand, as well as the repair and reconstruction of housing, foreign tourism, it is desirable to move beyond the corona crisis. as for food, the hypothetical progressive scale of taxation will not affect them. therefore, a more even distribution of income due to the progressive scale of taxation, even in such a rigid hypothetical version as the one given above, does not pose a serious threat to the middle class. not to mention the families of $ millionaires. depending on the situation, two models of anticrisis social support of the population are possible: ) maintaining the level of minimum incomes (salaries, pensions, benefits) due to their indexation and insurance; ) targeted social assistance to those in need. at the same time, social assistance can be provided in the form of unemployment benefits, support for large families, subsidies to enterprises for the payment of studies wages, etc. for example, a. kudrin proposed to increase the minimum wage and unemployment benefits by one year, to provide subsidies to businesses for the payment of wages, using the national welfare fund and financial markets [ ] . in addition to cash payments, assistance may come to those in need in kind: in the form of free meals, coupons for free food, medical care for the elderly, care for minors, etc. the creation of a second economic structure for the accelerated development of smes opens up wide opportunities for self-realization and self-protection of the population from the impending crisis. at the same time, public opinion should be prepared for upcoming economic difficulties, for inevitable moderation in consumption and demands. conclusions. so, in anticipation of a possible economic crisis, two types of proactive anticrisis measures are considered. economic measures. russia can oppose the possible reduction in economic activity under the influence of global market downturns, oil demand and prices, sanctions and a pandemic by the release of entrepreneurial initiatives by the population, local and regional authorities aimed at accelerating the growth of the supply of domestic consumer goods, domestic tourism services, production of aggregates, units and parts, components for cars, after-sales service of foreignmade aircraft and many other domestic goods and services, deputy importing. this "virgin land" of domestic business can be raised under the condition of a deep institutional reform aimed at creating a special economic structure for the development of smes. social measures. for the social protection of the population from the effects of the crisis, a progressive taxation scale widely known in world practice for highincome groups can be used. calculations show that the correct increase in taxes on high incomes of the population will create pent-up demand for durable goods, but at the same time it will reduce the negative impact of the crisis on the least protected segments of the population. rational redistribution of income in favor of the poor should not radically reduce the standard of living of the middle class. the redistribution of part of the income of the rich in favor of the low-income and poor as an anticrisis measure does not bear additional burden on the budget, does not require an increase in the money supply, and is not accompanied by an increase in inflation. ultimately, it can serve to strengthen the public sector. the social norm of the upcoming life of all segments of the population of russia should be moderation in consumer demands and ambitions. fal'tsman, problems in russia's economy until problems of forecasting in small and medium business economics according to academician ivanter the authors declare that they have no conflicts of interest. key: cord- - mapwlq authors: schulz, rodrigo a.; coimbra-ara'ujo, carlos h.; costiche, samuel w. s. title: covid- : a model for studying the evolution of contamination in brazil date: - - journal: nan doi: nan sha: doc_id: cord_uid: mapwlq in the present article we introduce an epidemiological model for the investigation of the spread of epidemics caused by viruses. the model is applied specifically to covid- , the disease caused by the sars-cov- virus (aka"novel coronavirus"). the sir (susceptible - infectious - recovered) model is used as a basis for studying the evolution of the epidemic. nevertheless, we have modified some of the model hypotheses in order to obtain an estimate of the contamination free of overestimated predictions. this extended model is then applied to the case of the recent advance of the epidemic in brazil. in this regard, it is possible to obtain the evolution for the number of infectious significantly close to that provided by current data. accordingly, we evaluate possible future scenarios for the disease spread. regarding the population susceptibility, we consider different social behaviors in response to quarantine measures and precautions to avoid contagion. we conclude that the future scenario of the epidemic depends significantly on the social behavior adopted to date, as well as on the contagion control measures. the extent of such measures would be likely to cause thousands, millions or tens of millions of contaminations in the next few months. the emergence of sars-cov- epidemic around the world has motivated a series of studies and projections for the evolution of the disease over the next few months. the fight against the spread of the disease occurs in the world by the use of many research techniques, treatments and the prevention of the contamination [ ] . in the latter case, one of the main factors associated with virus prevention is related to restrictions in human social contact in order to prevent the unrestrained contagion [ ] . however, the absence of a broad scientific literature on the evolution of the virus, as well as the accelerated growth of contamination in brazil during march , give rise to a series of possible predictions. when such predictions are disclosed by the main information vehicles, it is provided scope for minimalist and maximalistic interpretations of the case. in this aspect, adequate projections based on current data is needed. considering such circumstances, it is natural that epidemiological models arise driven by actual available data related to the evolution of the disease. once created the model, it is possible to predict possible future scenarios from which one can have a better indication of the dimension of such an epidemic in the country and in the world. some of the currently known models used in such procedures are sis, sir and sirs [ ] . the first one is used mainly in the study of diseases in which recovery does not prevent the re-contamination of the pacient, usually caused by bacterial agents [ ] . the second is used for modeling epidemics involving infectious diseases, such as covid- , caused by sars-cov- [ ] . the third one is basically used for the study of infections caused by influenza, since it allows the modeling of a situation where recovered individuals lose their immunity (which sir, for example, does not model) [ ] . the present work explores the building of a variation of the sir model in order to cover relevant conditions present in the brazilian context, such as: ) daily mortality and daily birth rates (which change, over time, the population) and ) the gradual reduction of the population susceptible to the disease in fuction of social distancing measures. here it will be considered a modification in the hypothesis that, initially, the entire population analyzed is susceptible to contamination by the disease. the brazilian situation until march had more than , confirmed cases of infection, with cases of death from the disease [ ] . the exponential growth of infection cases reveals the need to develop studies related to the behavior of epidemics in order to stabilize the current scenario, as well as to allow the advance in the development of tools that permit analyzing the behavior of epidemics in the future from the first cases. other relevant impact of such studies is that they provide concrete justifications for the effectiveness and awareness related to social distancing policies. the paper is divided in sections. the second section reviews the original formulation of the sir model. the third section presents the methodology and the forth section deals with the use of such a methodology in the brazilian case. the fifth and the final sections present some discussion, concluding remarks and prospects. the sir model is based in a simple hypothesis: the individual of a given population where an epidemic occurs goes through different stages of susceptibility to infection [ ] . such stages give rise to well defined compartments in the model, where the individual is classified as: from this hypothesis, an epidemic can be characterized as a flow: where the infectious i and recovered r population grow over time, while the susceptible s subject decreases over time. in this way, this flow can be described by functions s(t), i(t) and r(t) such that the evolution of i(t) over time characterizes the number of cases of infection at all times throughout the course of the disease. to characterize the temporal evolution of the model, it is necessary to establish how the instantaneous variation of the functions of the model occurs. for example, if α is the rate of change in the number of infectious individuals (the ratio of infectious to a previous time interval), then the number of new infections at each time interval, in a population of n individuals, reduces the susceptible population as follows: on the other hand, if β is the rate of recovery from the epidemic, then the number of recovered individuals will be a fraction of the number of infectious: at last, the number of infected each day should equal the difference between the number of new contaminations in the susceptible population and the number of recovered from the infected population, that is the sir model also considers that the initial value associated with the functions s(t), i(t) and r(t) can be defined assuming that, initially, the entire population is susceptible to infection, that there is a minimum population d, initially infectious (otherwise there would be no way for the epidemic to start), and there is no one recovered, since the epidemic did not started. in other words: in this way, the temporal evolution of the functions described by the sir model consists of an initial value problem involving a system of three ordinary differential equations. in the previous section, the sir model was presented as a proposal for modeling an epidemic. the system of equations is reasonably simple. however, its construction requires some hypotheses whose acceptance may imply an overestimated forecast of the number of people infected by the epidemic. are they: i -initially, the entire population is susceptible to contamination. ii -there are no deaths or births over the course of the epidemic. iii -there are no reductions in the susceptible population, for example, due to quarantine measures. those processes significantly interfere in estimating the number of people infected. in respect to i, for example, why should one suppose that the contamination of one person in são paulo on february would imply that someone in the state of roraima (∼ , km away) would be susceptible to contamination on february ? the susceptibility to contamination is directly related to the proximity between contaminated individuals, but in this case, if both are separated by long distances, without maintaining any contact, then there is no reason to suppose that there is a relationship of susceptibility between them. regarding ii, it is well known that several deaths of people, contaminated or not by the disease, occur throughout its evolution, interfering in the number of susceptible individuals. similarly, the more people born the more susceptible to contamination they become, promoting an increase in the number of cases. and in respect to iii, it is assumed that, with the evolution of the epidemic, people will begin to isolate themselves socially, whether by individual will or governmental determination, so that the susceptible population is also reduced due to this factor [ ] . this means that the forecast of the sir model is naturally overestimated to calculate the number of people infected daily on a value of s(t) which can be many times greater than the real one. to correct the problematic points in assertions i, ii and iii, one can add terms in the equations ( ), ( ) and ( ) in order to operate them according to the logic of a growing susceptible population, where there are reductions resulting from deaths and from social isolation processes, as well as an increase in the number of susceptible people due to the birth rate. given a population n , the sir model originally supposes that s( ) = n and s(t) < s( ), ∀t > . here, in order to correct the fact pointed out in i, it is supposed that s( ) = ( −ρ )n , where ρ is the percentage of the population initially isolated from contamination, and that ds(t) dt evolves so that the rate ρ decreases over time, i.e. where and ∆ρ is the mean rate of the growing of the susceptible population with the disease evolution. in this respect, the smaller the value of ρ is (a value between and ) the more the initial population approaches n . besides, the greater ∆ρ is the faster the susceptible population approaches the total population. for example, a reasonable estimate for ρ is to consider the initial susceptible population as the population of the place where the epidemic begins, taking the ∆ρ rate as the mean percentage of the growing of the susceptible population, parameterized by the total time required for the epidemic to reach all the domains of a given country. that is, if ∆t * is the time required for the epidemic to reach all the domains (states) of a country in which the epidemics occurs, then the mean number of new susceptible individuals in each day will be n = n ∆t * , and the percentage of new susceptible people each day will be ∆ρ = n n . in this case, ∆ρ can also be interpreted as the inverse of the period necessary for the epidemic to reach the whole country, because this change also implies that the number i(t) of contaminated individuals will increase at the same rate that s(t) decreases, that is, depending on the gradual increase in the susceptible population: to correct the value of the population susceptible to contamination due to deaths and daily births, just add terms to the equation ( ) that relate the mortality rate and the daily birth rate to the susceptible population s(t). that is, if γ is the percentage of the population that dies daily due to something unrelated to the epidemic, and θ is the daily rate of people that born in the place where the epidemic occurs, then the variation in the susceptible population will be proportional to the difference between the number of people who born and the number of people who die, i.e. where p (t) expresses the variation in the number of susceptible people, per day, due to mortality and birth rates. when adding p (t) to the equation ( ), we get it may happen that, after some period after the beginning of the evolution of the epidemic, there is a dramatic reduction in the population s(t) due to social distancing measures. the cancellation of classes in public schools and universities, commercial and industrial activities, as well as musical concerts and similar events are examples of how these reductions can occur. thus, it is possible that there is a time τ such that the susceptible population will be reduced with the rate k of its default value. when this occurs, the equation ( ) should start to consider the new population as the contingent under which the contamination factor α acts. to characterize this process, it is possible to define the functions s(t) and i(t) by parts, as follows: this process occurs in such a way that the population s(t) tends to increase with time, since ρ(t) decreases with time, but it also tends to decrease with the factor k (from τ ). that is, if the proportion k of people who begin to isolate themselves in quarantine is greater than the rate at which the susceptible population increases (parameterized by ρ(t)), then the epidemic will begin to decrease. on the contrary, if the rate at which people become susceptible is greater than the rate at which they become quarantined, then the epidemic process will continue to grow until it reaches its maximum. it is also possible to generalize this definition by parts so that, for each t , t , t , ..., t n where quarantine processes are started, one can respectively consider the factors k τ , k τ +∆t , k τ +∆t , ..., k τ +∆tn which act by decreasing the susceptible population. therefore, from the nth instant t, the equations ds(t) dt and di(t) dt will be considered under the form: the obtained system of equations, after the proposed modifications, can be summarized as follows: s( ) = n ; < ρ < ; i( ) = ; r( ) = ; α, β, γ, ∆ρ, k τ +∆tn ∈ r. a very simple way to find the solutions to the initial value problem is to obtain an approximation for the derivatives of s(t), i(t) and r(t) from the taylor series and, following the euler method, obtain the values of s(t + ∆t), i(t + ∆t) and r(t + ∆t) as follows: where ∆t is the step of the solution, determined by the upper and lower limits of the interval at which the solution is calculated , as well as the number of subdivisions in the n range, that is: so that the solution is calculated in the interval [t i , t f ]. in view of the reformulation of the sir model, we can consider its application to describe the evolution of the covid- epidemic. in brazil, it can be considered that it started on february , [ , , ] . first, it is necessary to characterize the parameters that define the evolution of the epidemic in the country. the brazilian population is among the largest in the world, with around , , people [ ]. thus, for simulating the evolution of the epidemic in brazil, it can be assumed that: n = , , people. in addition, for the simulation, it is assumed that the mortality rate in the country follows the global annual rate of . / , people per year [ ] . in order to simulate a daily see the appendix evolution, the daily percentage rate corresponding to the number of deaths per year must be considered: γ = . , × days = . × − day . regarding the birth rate, brazil registered , , births in , according to data from ibge (brazilian institute of geography and statistics) [ ] . in this way, the mean daily birth rate, defined in terms of the data, provides a daily birth rate given by θ = , , , , × days ∼ = . × − day . according to information released by the adolfo lutz institute, the first confirmed case of covid- in brazil occurred on february , , in the case of a patient who was in são paulo [ ] . thus, since it is necessary to assume a minimum initial value of contamination to evolve the epidemic, the simulation will occur from february th to the current date. therefore, being sure of the first contamination, and the active action of the contaminated person in relation to the spread of the virus, for the simulation, it is assumed that d = , t i = → february . as the patient was in the state of são paulo, it is reasonable to assume that the population initially susceptible is that of the state itself. thus, it is assumed that ρ (the population initially free from contamination) is the total population, except for the population of the state of são paulo, about % of the brazilian population [ ] . so: in addition, until march ( days after the outbreak of the epidemic), the ministry of health recognized that community transmission of the virus had reached the entire country [ ] , so that the period required for susceptible population to reach the entire country is days, and thus, from equation ( ): finally, it remains to determine the values of α and β from the current scenario of the epidemic in brazil. according to data obtained by the worldometer [ ] platform, brazil had, until march , the number of , confirmed cases of covid- distributed in the time series illustrated in figure . [ ] . the mean growth rate α is defined as the mean of the ratios of the number of cases on the following day in relation to the previous day. that is, in this case: where n = corresponds to february , and n = corresponds to march . for the recovery factor β, a similar procedure is performed, considering the mean of the ratio of the number of recovered to the number of contamination cases. due to the unavailability of the data, however, it is assumed that the brazilian recovery factor follows the world average [ ] , i.e. finally, it is also assumed that, starting on march , there are five factors (k , k , k , k , and k ) that make it to be reduced by %, %, %, %, and more % on march , march , march , march , and march , respectively . these values are arbitrary due to the lack of concrete data about how many people are in fact isolated from contamination by quarantine, and express the trend, from these dates, of the reduction of contamination determined by the variations in the the curve illustrated in figure . considering these data, the result of the simulation between february and march is illustrated in figure . given the satisfactory adjustment close to the curve of real data, one can consider the extent of the simulation results for the future. however, as there is currently no specific scenario regarding the factors of reduction of the susceptible population due to social distancing measures, several possibilities can be explored. the first of these is not to consider, from april onwards, that social isolation measures are taken, that is, to remove the k factor from the th day of the disease evolution (corresponding to the st of march). two other possible cases can be explored by imposing conditions of future social distancing, in order to verify the effect of such measures. figure shows the evolution of the epidemic for the first case, where there are no restrictive measures in the future, and two other cases where the population promotes social isolation keeping it at % until the end of the epidemic and, lastly, raising the percentage of the quarantined population by % from april , that is, the comparison between the absence of social isolation measures, and measures reaching % and % of the population, respectively in the first case, a worrying scenario occurs, where the peak of contamination reaches practically % of the population on april . in the second case, the % reduction in the susceptibility of the population results in a peak of contamination that reaches around . % of the brazilian population on may , which consists of a considerable reduction in relation to the first case. in the latter case, with isolation conditions reaching % of the population, this peak of cases reaches about % of the brazilian population, on june . these results show how social distancing measures alter the dynamics of the epidemic in the country in order to decrease the peak and the total number of cases, as well as to extend the time necessary for the epidemic to reach a maximum in the number of contaminations. additionally, these results may raise the following question: given an instant τ , how restrictive should social isolation measures be? that is, what is the best estimate for the value of k τ ? in section . . we showed how it is possible to consider population reduction rates as a result of social isolation measures. so that, for the instant τ , it follows one way to estimate the value of k τ in this case is to make the number of new contaminated individuals null, i.e. this condition does not guarantee that new contamination will cease to occur completely, since it would be necessary to keep the entire infected population in isolation, which is not taken into account by the model, and may often not be a measurable data from the country's statistics. in theory, if all people infected by the epidemic are known, then it would not be necessary that the social isolation condition to extend to the susceptible population. however, in cases where an emerging epidemic begins to evolve and the actual number of infected people is not known, the equation ( ) is the best estimate for how restrictive measures of social isolation should be. in the case of brazil, taking march ( days after the epidemic started), march ( days after the epidemic started) and april ( days after the epidemic started) as a reference, we obtain respectively the values: thus, it is possible to note that the longer the time at which social isolation measures are implemented, the more restrictive they must be in relation to the number of people quarantined. thus, given a very long period of time, the value of k τ will require that the entire population establish measures of social isolation, since because ∆ρ is always greater than zero. these three possible future scenarios are consistent with the actual situation of the epidemic in brazil. that is, with respect to the actual data available to date, the three scenarios are possible and depend exclusively on how future actions related to social behavior will be taken. in this respect, the development of epidemiological models capable of predicting the evolution of the epidemic in the face of social behavior is an important tool for raising awareness, shedding some light on many aspects of the disease pattern and providing strength to the scientific dissemination about the importance of the social responsibility involved in quarantine measures. after all, apparently, although other epidemics may arise in the future, more or less severe than that caused by sars-cov- , the results of such natural phenomena, in terms of the number of infected and dead individuals, depend essentially on human behavior and the priority given to the processes of reducing susceptibility. the results obtained from modeling the sars-cov- epidemic evolution in brazil allow one to draw up estimates and predictions for the future scenario of the disease progress in the country. as discussed, both scenarios -the worrying and the controlable -are possible and compatible with the current data. in this context, dissemination of scientific facts and awareness-raising campaigns are of paramount worthness, shedding some light on the importance of isolation policies during epidemic situations. in this article, we reformulated the sir model to comply with the hypotheses of a susceptible population that grows over time and varies with mortality and birth rates. as well as being able to model susceptibility reductions in function of social measures for controling the epidemic advance. we explored the case of the epidemic evolution in brazil, a worth issue since it could mean, given the characteristics of the country, a considerable impact on the global economy, not to mention the serious consequences to the country's economic and social structure. we conclude that, within the social and economic possibilities of the country, it is prudent to foster the maintenance of quarantine policies in order to avoid mass contamination of the population in april, . nevertheless, the daily updating of data linked to the current situation of the country must be perpetuated, since, for many reasons, it is possible that, to the date, the number of cases are underestimated and, thus, the forecasts provided here may change significantly due to new updates of the real situation in the country. ti = input ('enter the start time value: '); n = input ('enter the number of subdivisions of the time range: '); dt = (tf-ti)/n; t = ti:dt:tf; % constants alpha = input ('enter the average value of the contamination rate: '); gamma = input ('enter the current death rate value: ') beta = input ('enter the average recovery rate: '); d = input ('enter the number of initial patients: '); p( ) = input ('enter the starting value of the percentage of the population free from contamination: '); deltap = input ('enter the value of the percentage reduction of the contamination-free population per day: '); n = input ('enter the population value: '); k( ) = input ('enter the period until % of the population is quarantined: '); k( ) = input ('enter the period until % of the population is quarantined: '); k( ) = input ('enter the period until % of the population is quarantined: '); k( ) = input ('enter the period until % of the population is quarantined: '); k( ) = input ('enter the period until % of the population is quarantined: '); %initial conditions s( ) = n; r( ) = ; i( ) = d; %evolution of the susceptible population for i= :n p(i+ ) = p( )*power(( -deltap),(ti + i*dt)) if (p(i+ ) < . ) p(i+ ) = end end %iteration for i= :n if (i< round(k( )/dt)) sder(i) = ((-alpha*i(i)*(s(i)*( -p(i))))/n)-((gamma-theta)*s(i)); rder(i) = beta*i(i); ider(i) = (((alpha*i(i))*(s(i)*( -p(i))))/n)-(beta*i(i)); r(i+ ) = r(i) + rder(i)*dt; i(i+ ) = i(i) + ider(i)*dt; ylabel ('recovered people (n o of people)') sobre a possibilidade de interrupção da epidemia pelo coronavírus (covid- ) com base nas melhores evidências científicas disponíveis plano de contingência do estado de são paulo para infecção humana pelo novo coronavírus - -ncov. secretaria de estado da saúde modelos matemáticos aplicadosà epidemiologia. faculdade de economia universidade do porto, tese de mestrado essential mathematical biology mathematical epidemiology population biology of infectious disease: part i secretaria estadual de saúde do rio grande do sul as medidas de quarentena humana na saúde pública: aspectos bioéticos department of economic and social affairs, population division genoma do sars-cov- do primeiro caso de covid- da américa latina sequenciado em horas pelo instituto adolfo lutz coronavírus: mortes e . casos confirmados coronavírus cases: brazil s(i+ ) = (s(i) + sder(i)*dt) else if (i > round(k( )/dt)) && (i < round(k( )/dt)) i)- . )))/n)-((gamma-theta)*s(i) rder(i) = beta*i(i) i))*(s(i)*( -p(i)- . )))/n)-(beta*i(i) r(i+ ) = r(i) + rder(i)*dt i(i+ ) = i(i) + ider(i)*dt s(i+ ) = (s(i) + sder(i)*dt) else if (i > round(k( )/dt)) && (i < round(k( )/dt)) i)- . )))/n)-((gamma-theta)*s(i) rder(i) = beta*i(i) i))*(s(i)*( -p(i)- . )))/n)-(beta*i(i) r(i+ ) = r(i) + rder(i)*dt i(i+ ) = i(i) + ider(i)*dt s(i+ ) = (s(i) + sder(i)*dt) else if (i > round(k( )/dt)) && (i < round(k( )/dt)) sder(i) = ((-alpha*i(i)*(s(i)*( -p(i)- . )))/n)-((gamma-theta)*s(i)) rder(i) = beta*i(i) i))*(s(i)*( -p(i)- . )))/n)-(beta*i(i) r(i+ ) = r(i) + rder(i)*dt i(i+ ) = i(i) + ider(i)*dt s(i+ ) = (s(i) + sder(i)*dt) else if (i > round(k( )/dt)) && (i < round(k( )/dt)) sder(i) = ((-alpha*i(i)*(s(i)*( -p(i)- . )))/n)-((gamma-theta)*s(i)) rder(i) = beta*i(i) i))*(s(i)*( -p(i)- . )))/n)-(beta*i(i) r(i+ ) = r(i) + rder(i)*dt i(i+ ) = i(i) + ider(i)*dt s(i+ ) = (s(i) + sder(i)*dt) i)*( -p(i)- . )))/n)-((gamma-theta)*s(i) rder(i) = beta*i(i) i))*(s(i)*( -p(i)- . )))/n)-(beta*i(i) r(i+ ) = r(i) + rder(i)*dt i(i+ ) = i(i) + ider(i)*dt s(i+ ) = (s(i) + sder(i)*dt) i( ) for i= :tf i_per_day(i) = i(i*( /dt)) end plot (t_in_days,i_per_day) title ('infected x time') xlabel ('time (days)') ylabel s_per_day ( ) = s( ) for i= :tf if (i< round(k( )/dt)) s_per_day(i) = s(i*( /dt))*( -p(i*( /dt))) else if (i > round(k( )/dt)) && (i < round(k( )/dt)) /dt))*( -p(i*( /dt))- . ) else if (i > round(k( )/dt)) && (i < /dt))*( -p(i*( /dt))- . ) else if (i > round(k( )/dt)) && (i < /dt))*( -p(i*( /dt))- . ) else if (i > round(k( )/dt)) && (i < /dt))- . ) else s_per_day(i) = s(i*( /dt))*( -p(i*( /dt))(t_in_days,s_per_day) title ('susceptible x time') xlabel ('time (days)') i= :tf r_per_day(i) = r(i*( /dt)) end plot (t,r) title the algorithm used to solve the system of ode's was formulated in mat lab language, and it is configured as follows:%algorithm: covid- in brazil %domain tf = input ('enter the ending time value: '); key: cord- - iv fdof authors: hori, keiko; saito, osamu; hashimoto, shizuka; matsui, takanori; akter, rumana; takeuchi, kazuhiko title: projecting population distribution under depopulation conditions in japan: scenario analysis for future socio-ecological systems date: - - journal: sustain sci doi: . /s - - - sha: doc_id: cord_uid: iv fdof this study develops a projection model of future population distribution on the basis of japan’s current depopulation trend and applies this model to scenario analyses that assume population compactification and dispersion. the model enables a description of population migration at two levels. first, municipal populations are projected using the cohort-component method, and second, the spatial distribution of populations within municipalities is projected at a m grid resolution with the use of the gravity model. based on the japanese depopulation context and the country’s national spatial strategy, the compact scenario predicts the formation of medium-scale regional urban areas (population centers located across japan) and the concentration of people on high-density population areas within municipalities. meanwhile, the dispersed scenario predicts the formation of more but smaller regional urban areas and the dispersion of the population to low-density areas. the simulated population distribution for reveals spatial change in population density and age structure, as well as an abundance of areas that were inhabited in but will be zero population areas by . overlay analysis of future land use maps and the simulated population distribution maps can contribute toward identifying areas where natural capital such as farmland and forest plantation should be managed but where there will be significant population loss by . electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. in contrast to the population growth trend in much of the developing world, aging and depopulation have emerged as two important issues in many developed countries. according to united nations population division (unpd), "unprecedented" aging is a pervasive global phenomenon, and an increasing number of countries are experiencing population decreases because of sustained low fertility or emigration (united nations population division ). among the countries where population shrinkage is expected, japan faces the most serious depopulation and radical demographic transition (eberstadt ; matanle et al. ) . it is expected that by , japan's population will have decreased to million from a population of million in (national institute of population and social security research: ipss ). the causes of depopulation stem from delayed marriage and a decline in birth rate relative to the increment of working women and diversified values in life (cabinet office ) . this trend has been accelerated by the outflow of young people from rural to urban areas, where women are frequently isolated and thus face difficulty in obtaining support for raising children (japan policy council ) . depopulation has expanded from rural and remote areas to suburban and urban areas (matanle et al. ) , and the ministry of land, infrastructure, transport and tourism (mlit) estimates that % of inhabited areas across the country will experience % or greater population loss by (mlit a) . intertwined human societies and ecosystems constitute the interdependent socio-ecological system, in which ecosystems provide necessary services for human well-being, supported by sustainable resource utilization and management by human society (colding and barthel ; duraiappah et al. ) . population change is a significant indirect driver of ecosystem change, impacting the ecosystem through changes in local land use patterns (matanle et al. ; ma ) . the abandonment of land and property is inevitable in areas undergoing depopulation, leading to serious damage to natural capital (the stocks of natural resources consisting of ecosystems) that provides ecosystem services (matanle et al. ; karcagi-kovats and katona-kovacs ) . the ministry of agriculture, forestry and fisheries (maff ) and the ministry of the environment (moe ) reported that the decrease in the number of people who can engage in the primary industries led to increased abandoned farmlands and degraded forests within the depopulated and aging rural communities of japan. such underuse and undermanagement of natural capitals have been recognized as crises that drive biodiversity loss and the decline in ecosystem services (moe ; ohsawa et al. ) . urban shrinkage has also become a significant research agenda for the social and land use sciences (haase et al. ) . however, if abandoned land is managed for rewilding, it is possible that such designed "new nature" can provide various ecosystem services (gross ; navarro and pereira ) . thus, to plan appropriate management strategies to maintain and recreate sustainable socio-ecological systems at the local scale, projections of future population distribution with high spatial resolution are essential. city shrinkage is a multi-layered process caused by various patterns of out-migration. therefore, spatially estimating feasible demographic structures is problematic (gross ; feldhoff ) . matanle ( ) argues that internal migration in japan, leading to both rural and urban shrinkage, can be understood at four levels of movement: inter-regional (sub-national), inter-prefectural, inter-municipal, and intramunicipal. although complexities and uncertainties about social processes exist, an experimental approach should be used to project future population distribution and ecological design requirements (gross ) . scenario analysis which seeks plausible futures with multiple assumptions about demographic and development trends has been widely recognized as an experimental approach to the development of national spatial strategies (daly and kitchin ) . of significant importance to an exploration of the impact on ecosystems is the question of whether a shrinking society will lead to population compactification or dispersion. this question has led to dominant and contradictory theories about sustainable urban forms (holden and norland ) , and can be rephrased as intensive development (or settlement) within a small area or extensive development over a large area (soga et al. ) . as a movement related to compactification or dispersion thus far in japan, the continued outflow of people from rural to urban areas and expansion of urban areas, including suburban areas, have occurred due to industrialization and urbanization during the era of high economic growth after world war ii (feldhoff ; matanle ) . relocation to outside of metropolitan areas has been promoted for industries and population to mitigate constant population loss in rural areas since the s (cabinet office ). thereafter, the necessity of development with compactification has been the subject of debate since the s in response to progressive risks, such as a decline in the working population and intensification of environmental problems (ohashi and ishizaka ; murayama ) . the compact society and the dispersed society have different ecosystem impacts. for example, continuous forested or green spaces can be maintained under compact development, enabling the conservation of local biodiversity (sushinsky et al. ; gagné and fahrig ) . a dispersed society, on the other hand, provides populations with access to nature and opportunities to reconnect with nature, and promotes the utilization of local natural resources through agriculture and forestry (scott et al. ; moe ) . given the different impacts on socio-ecological systems, projecting population distribution under processes of compactification and dispersion is very important. a review of previous research that models future population distribution reveals a common approach to nation-wide spatial population distribution. multiple-step simulation processes, for example, at the state or municipal level and at the grid level, have been applied to express compactification and dispersion. wissen et al. ( ) projected future population distribution in switzerland using four scenarios in two steps: the allocation of municipal population gain and loss, and settlement distribution modeling at m resolution. the u.s. environmental protection agency (epa ) estimated state level populations using the cohort-component model as a first step, and then simulated spatial allocation of housing density using the gravity model at ha resolution. thorn et al. ( ) simulated decadal change in population density in new hampshire for - by incorporating municipal population allocation and the allocation of -m grid cells using cost distance-weighted gravity model. although these studies share some common approaches, none had depopulation trends as a baseline assumption. daly and kitchin ( ) characterized decline-oriented planning as a spatially selective approach to cost-effective redevelopment, unlike the growth-oriented planning of "distribution" under circumstances of quantitative increase. ohashi et al. ( ) argue that population decrease involves quite complex processes meaning that it cannot always be explained by the same simple mechanisms that express population growth. given these arguments, an appropriate method must be used to project spatial population distribution trends under conditions of serious population decline in japan. in the japanese context, ariga and matsuhashi ( ) and matsui et al. ( ) have attempted to project population distribution by applying compact and dispersed scenarios while assuming a fundamental depopulation trend. however, these studies only modeled population distribution within municipalities or prefectures and did not adopt multi-scale simulations, such as the common processes observed in previous studies. as mentioned above, four levels of internal migration (from inter-regional to intra-municipal) have been observed to cause population decline in japan (matanle ) . this suggests that developing a new projection method to express both inter-prefectural or inter-municipal and intra-municipal migration under depopulation trends would make a significant contribution to a more realistic scenario analysis of depopulation in japan. the aim of this study was to develop a population distribution projection model under conditions of depopulation, expressing migration at multiple levels, to conduct scenario analyses that assume compactification and dispersion of japan's population. this study also explored the availability of human labor for the sustainable management of natural capital, such as the maintenance of farmland and secondary forest, and this paper proposes sustainable design strategies for future socio-ecological systems in japan. the developed model presents japan as a "pioneer" country with crucial and ongoing depopulation challenges and aims to provide useful insights for other asia-pacific and european countries experiencing depopulation. to explore plausible natural capital and ecosystem service futures across japan, the pances (predicting and assessing natural capital and ecosystem services through an integrated social-ecological systems approach) project developed four scenarios (pances ; saito et al. ) using the scenario axis method (klooster and asselt ) . these four scenarios were situated on two axes: ( ) future society will have a "natural capital base" that promotes ecosystembased infrastructure development and land management, or a "produced capital base" that depends more on human infrastructures and technologies; and ( ) population concentration will advance toward "urban compactification", with populations concentrated in compact cities and the rewilding of underutilized land, or there will be less concentration, leading to a decentralized society with "dispersed populations" maintaining rural communities. as part of the pances project, matsui et al. ( ) developed a simulation model for population spatialization under the second axis of urban compactification versus dispersed population. this model applied a gravity-based population allocation algorithm at km resolution to express migration within prefectures. to improve the reality of population distribution and spatial resolution, the study presented in this paper adopts a new process to express migration at multiple levels. under full-blown population decline, japan's national land concepts are as follows: "development of national land promoting interaction-led regional revitalization" and "multi-layered and resilient compact and networked structure" (mlit ) . these concepts present a vision of the concentration of infrastructure, services, and industries in specific areas that hold a certain population size throughout japan. it is a vision of regional revitalization and innovation triggered by the active interaction of people, goods, money, and information from different areas, such as between urban areas and rural areas. in particular, this vision seeks to mitigate the continuous net outflow of residents from rural areas to tokyo, where the fertility rate is lowest, as such migration has intensified rural population decline, leading to increased depopulation. measures to realize a multi-layered "compact and networked structure" vary depending on regional scale and characteristics (mlit ) . to stem population flow from rural to metropolitans, especially to the tokyo, osaka, and nagoya metropolitan areas, the promotion of regional urban areas is required. regional urban areas indicate areas outside of metropolitans becoming population or business centers around which vigorous local economic and residential bases can form. the ministry of internal affairs and communications (mic) has already taken some steps to promote such regional centers. for example, regional cities with populations greater than , have been promoted by mic as centers of high level service function and business called "core regional urban areas (mic a)", while cities with populations of more than , and surrounding municipalities have been named "self-support settlement region (mic b)", and proposed as centers of small clusters of settlements. it has been recommended that different scales or types of population centers are formed as regional urban areas based on existing city scales in each region. with regard to population distribution within municipalities, mlit ( ) has proposed the formation of compact cities by concentrating urban functions and settlement within existing urban centers, and developing "small stations" in rural areas that will provide life-services to surrounding communities. in addition, a movement to promote a return to rural living, including in depopulated areas, has also been suggested as an alternative approach to stem depopulation. given these national strategies, this study developed a projection model of japanese population distribution using two projection steps (fig. ) . the first municipality resolution model expressed different formations of population centers as realistic scenarios under depopulation conditions. new migration trends were assumed to occur beyond prefectural boundaries and subnational blocks. in the compact scenario, this study assumed medium-scale (smaller than major metropolitan) regional urban areas with populations of more than , , corresponding to "core regional urban areas" (mic a). in the dispersed scenario, municipalities of more than , were assumed to form smaller but more regional urban areas, corresponding to "self-support settlement region" (mic b). based on the u.s. environmental protection agency (epa the second step of the model reproduced the population distribution at a m grid resolution by population density projections using the arranged gravity model based on previous research (epa ; thorn et al. ; matsui et al. ) . in this study, the compact scenario assumed population concentration in high-density areas within municipalities. in the dispersed scenario, the dispersion or return of people to low-density areas was assumed in the nation-wide simulation. by way of prefectural case study, a further analysis of the formation of small population centers in rural areas to maintain community functions was conducted. in the final step, an overlay analysis of projected population distribution and future land use and land cover (lulc) map was conducted to spatially examine the availability of labor for the management of natural capital, such as the maintenance of farmland and secondary forests. this analysis was conducted so that the projected population maps can contribute to the design of appropriate sustainable socioecological strategies. as with the pances scenarios , population distribution projections were conducted to , based on data from japan's national population census. the municipal population was projected according to sex and -year age groups, using the cohort-component method with -year steps as shown in eqs. ( ) and ( ), referring to regional population projections for japan: - (ipss ): where p t,i,j,k is the population of municipality k ( - , for each city, town, village, special ward, and administrative district of ordinance-designated cities ) in year t ( - ), by -year age group i (i = [age - ]- [over age ]) and sex type j (j = [male] and [female]). ( ≤ s ≤ ) and m t− →t,i− →i,j,k (− ≤ m) express survivorship rates in municipality k and net migration rates to municipality k of -year age group i − from year t − to year t by each sex type j. a minus m value means the outflow of population from municipality k exceeds inflow. c t,k and b t,j,k are, respectively, child-woman ratios (average population of the age group - per woman in the age group - ) and sex ratios for the population of age group [age - ] of municipality k in year t. the baseline municipal population and the parameters to project future population (s, m, c, b) were cited from the population census (statistics bureau of japan: sbj ) and regional population projections for japan: - (ipss . the to parameters (ipss ) were utilized again to project the to municipal population. municipal migration rates were adjusted for each scenario. in the compact scenario, by referring to the requirements and actual examples of a central city of "core regional urban areas" (mic a), municipalities with populations greater than , and daytime/night-time population ratios (sbj ) of more than . were selected as regional urban centers. ordinance-designated cities were judged by the total population of administrative districts constituting the city. in contrast, based on the central city's requirements of "self-support settlement region" (mic b), municipalities located outside of japan's three major metropolitan areas, with populations of more than , , and with daytime/night-time population ratios of more than were selected as regional urban centers in the dispersed scenario. these central cities and their adjacent municipalities (described as municipality group a) were assumed to form regional urban areas, and the migration ratios of these municipalities were enhanced according to the following equation: where ṁ t− →t,i− →i,j,k∈a is adjusted migration rate of -year age group i − to municipality k∈a from year t − to year t by each sex type j. α (α > ) is a parameter for each scenario to determine the strength of population concentration in regional urban areas. increased population flow into group a municipalities was assumed to come from municipalities not included in group a. the migration rates of these other municipalities were decreased according to the following equations: where ṁ t− →t,i− →i,j,k∉a is adjusted migration rate of -year age group i − to municipality k∉a from year t − to year t by each sex type j. β t− →t,i− →i,j (β > ) is a dependent variable calculated by α to express the degree of additional population outflow from the municipalities outside of the regional urban areas. considering the significance of expressing diverse of scenario assumptions, including extreme and plausible population distribution , extreme and middle degree population concentrations into regional urban areas were expressed by adjusting parameter α. table summarizes the municipality resolution scenario assumptions. the grid resolution nation-wide population distribution was projected by allocating projected municipal populations into where p ,i,j,k,l and r ,i,j,k,l express the population of grid l belonging to municipality k and the population ratio of grid l to total population of municipality k in , by -year age group i and sex type j. r ,i,j,k,l was calculated corresponding to each scenario assumption. in the compact scenario, concentration in densely populated areas within municipalities was assumed, and in the dispersed scenario, dispersion to low-density areas within municipalities was assumed. for each municipality, age group, and sex, grids with an expected increased population ratio (grid group [a]) were extracted. grids with a higher ranked population ratio in were selected as grid group [a] for the compact scenario, and those with lower ranked population ratio (grids with accumulated population ratios up to γ( < γ < ) were selected as grid group [a] for the dispersed scenario. γ is a threshold for each scenario to determine which grids are expected to experience an additional inflow of population; outflow of population is assumed in the others. r i,j,k,l∈a was calculated according to the following equation: where δ ( < δ) is a parameter for each scenario to determine the increment degree of population ratio of grids included in group [a] . the population ratios of grids not included in group [a] were evenly decreased according to the following equations such that the population ratio could be totaled to within the municipality: where ε i,j,k ( ≤ ε ≤ ) is a dependent variable expressing the decrement degree of population ratios of grids not included in group [a] for each municipality k, age group i, and sex type j. the parameters for all scenarios in this grid resolution model are summarized in table . with regard to γ, a larger value was set in the compact scenario than in the dispersed scenario. this is because the population is unevenly distributed and concentration to a limited area (ariga and matsuhashi ) and, in general, the cumulative probability of ( ) p ,i,j,k,l = p ,i,j,k * r ,i,j,k,l , ( ) r ,i,j,k,l∈a = r ,i,j,k,l∈a * , r ,i,j,k,l∉a = r ,i,j,k,l∉a * i,j,k , population density shows a bow-shaped curve extending to the lower right [the lorenz curve (lorenz ) ]. the compact scenario had a larger γ threshold because the number of grids in which population ratio increased was less than in the dispersed scenario when the same thresholds were used. consistency between scenarios was maintained by the total number of population ratio with changed distribution [calculated by multiplying γ and (δ − )]. additional processing was conducted at the end of the grid resolution projection to enable comparison with the business as usual (bau) scenario for projected by mlit ( b) . the population of grids projected to be inhabited by very small populations was replaced with using the following equation, based on mlit ( b): where ṗ i,j,k,l,l′ is the population after the replacement process in the -m grid l constituting -km grid l′ (each -km grid consists of four -m grids) belonging to municipality k in , by -year age group i and sex type j. those m grids where the population of all age groups and both sex types were replaced by were considered "zero population grids". after processing, the population of grids not judged to be "zero population grids" were adjusted to fit the total municipal population for . in addition to the nation-wide projection, an additional projection for the dispersed scenario was conducted that focused on ishikawa prefecture. although flat dispersion of the population to low-density areas was expressed in the nation-wide grid resolution model, the japanese government has proposed the formation of "small stations" as central communities to maintain the vital life services in rural areas. under this strategy, population concentration in these small stations is expected to be a probable and realistic trend. according to the cabinet office ( ), small stations should be formulated in each elementary school district or each former municipal area. in the s, s, and s- s, japan experienced dramatic mergers of its municipalities (mic c). the significance of a multi-locational system that maintains functions in former municipal centers has been suggested as a means to prevent drastic population outflow from rural areas (buhnik ) . considering this context, population distribution with the formation of a population center in each former municipal area was projected under the dispersed scenario. this additional model is hereafter referred to as the former municipality model. ishikawa prefecture was targeted for the application of the former municipality model. this prefecture is located on the sea of japan coast, in the middle of honshu, japan's main island (fig. ) . the prefecture's municipalities vary in type (ishikawa prefecture a), and include kanazawa city, with a population of more than , (kanazawa city), and the rural municipalities on the noto peninsula, which have been selected by the food and agriculture organization of the united nations (fao) as a globally important agricultural heritage system (fao). ishikawa prefecture is a case study site of the pances project. although hashimoto et al. ( ) have attempted a scenario analysis of land use and ecosystem services on noto peninsula, population distribution did not fully consider the local demographic situation. given this background, ishikawa prefecture was selected as a case study site to explore the former municipality model. using data, populated grids in ishikawa prefecture were targeted as grids into which future populations could be allocated. the boundary data of former municipalities were obtained from national land numerical information, administrative zones data (mlit ). the municipal boundaries in place in were used as the boundaries of former municipalities (see fig. ). this additional projection was conducted only for the dispersed scenario based on the nation-wide projection of the population at the m grid resolution (p in eq. ( )). this model expressed the concentration of flatly dispersed population in the central areas of former municipalities with no change to the total population of former municipal areas, according to the following equations: where p′ ,i,j,k′,l and r′ ,i,j,k′,l express the population of grid l belonging to former municipality k′ and the population ratio residing in grid l to the total population of former municipality k′ in , by -year age group i and sex type j. as grids with concentrated population were named grid group [a′] in the former municipality model, higher ranked grids in population ratio r′ [grids with a accumulated ( ) p� ,i,j,k � ,l = ∑ l,k � =k � p ,i,j,k � ,l * r� ,i,j,k � ,l k � = , , …k � … , fig. location, overview, and municipal boundaries of ishikawa prefecture population ratio of no more than γ′( < γ′ < )] in were selected for each former municipality. γ′ is the threshold dividing the grids in group [a′] from others within the former municipality, and δ′( < δ) expresses the incremental degree of population ratio of grids included in group [a′] . as γ′ and δ′, . and . were set for both extreme and middle cases. finally, the same replacement process as shown in eq. ( ) was conducted. as argued in "background" , depopulation in areas holding natural capitals, such as agricultural land and forests, causes a decrease in labor to maintain and manage such capitals, which leads to their underuse or abandonment (maff ; moe ) . the locations where such problems are likely to occur are dependent on future population distribution and land use. thus, the study spatially examined the labor availability for natural capital management by overlaying the projected population distribution map and future land use map. lulc maps, developed according to shoyama et al.'s ( ) method, were used to conduct the overlay analysis. the maps correspond to four pances scenarios at the m grid resolution. the data consisted of categories: residential area, paddy field, cropland, other agriculture lands, abandoned farmland, grassland and bush, natural forest, secondary forest, plantation, and others. the lulc maps of the "natural capital-based compact society (nc)" scenario and the "produced capital-based compact society (pc)" scenario were overlaid by the population map of the extreme case compact scenario, while the lulc maps of "natural capital-based dispersed society (nd)" scenario and "produced capital-based dispersed society (pd)" scenario were overlaid by the map of the extreme case dispersed scenario. the land use category occupying the largest area of each -m grid of the population map was identified for each of those grids as their land cover attribute. among the categories on the lulc map, paddy field, cropland, other agriculture lands, grassland and bush, secondary forest, and plantation were considered to be lands in need of human management [hereafter referred to as mnc (managed fig. summarized results of nation-wide population distribution projection natural capital lands)]. across the country, scenario differences for populations living in the grids covered by the mnc were analyzed to provide an overview of changes in labor availability for the management of local natural capital. mnc grids projected to have high levels of depopulation (particularly zero population grids) and aging (more than half of residents aged over ) were spatially identified for ishikawa prefecture. the resulting population distribution and statistical data for each scenario are summarized in fig. . due to limitations of space, only extreme cases are described, with medium-range cases provided as supplemental materials in online appendix . total population resulted in an increment of approximately , in the compact scenario, and a decrement of , in the dispersed scenario. this was derived from differences in original migration rates by type of municipality. the population of each municipality was calculated by eq. ( ). the population of larger municipalities with comparatively higher migration rates increased in the compact scenario, and the population of smaller municipalities with lower migration rates, including minus values, increased in the dispersed scenario. that is the reason why total population under scenarios differed from bau. these differences can be interpreted as the rise and fall of population flow between japan and other countries. as the third row of fig. shows, the compact scenario resulted in more polarized population sizes in municipalities, with an increase in the number of municipalities of less than and those of more than , , while the number of mid-sized municipalities decreased compared to bau. in the dispersed scenario, a slight increase in the number of municipalities with more than , and less than , was observed. in the grid resolution, the number of zero population grids increased by approximately % from bau in the compact scenario and decreased by % in the dispersed scenario. zero population grids tended to appear on the fringes of inhabited area, and were especially prevalent in the hokkaido block and the chugoku block in the compact scenario (fifth row of fig. ). the formation of smaller population centers across japan were reproduced in the dispersed scenario. the number of grids with a population density of less than and more than increased in the compact scenario compared to the bau (sixth row of fig. ). in contrast, under the dispersed scenario, population density could be maintained at the medium level, i.e., with more grids in the - people/grid range compared to bau. the results of statistical analysis of ishikawa prefecture's population distribution, including the outcome of the former municipality model, are summarized in fig. . the number of zero population grids increased by approximately % from bau in the compact scenario and decreased by approximately % in the dispersed scenario. in the former municipality model dispersed scenario, the number of zero population grids was also less than for bau or the compact scenario. only kanazawa city and its adjacent municipalities were selected as the regional urban area to form a population center in the compact scenario, while in the dispersed scenario, nanao city and its adjacent municipalities on noto peninsula (location is shown in fig. b) were also assumed to form regional urban areas. nanao city and its surrounding areas maintained a larger population in the dispersed scenarios compared to the compact scenarios (fourth row of fig. ). in areas indicated by yellow circles, the former municipality model resulted in comparatively higher density grids in each former municipality area. for kanazawa city, urban residential sprawl is a serious issue for city planners (ishikawa prefecture ). thus, the results of progressive concentration in the city center under the compact scenario and former municipality model dispersed scenario were deemed more desirable. the number of grids by population density resulting from the former municipality model was positioned between the compact and dispersed scenarios for nation-wide projection and was close to the bau result (bottom of fig. ) . however, the number of grids with a density between and people/grid was larger than that of the bau, reflecting the maintenance of smaller population centers. based on the nation-wide results of the overlay analysis, fig. shows the number of grids covered by mnc by population density. the legend indicates the two scenarios, namely overlaid population distribution map and lulc map. the reason for the change in the number of grids is due to changes to certain types of land use, such as paddy fields or plantation forests, based on scenario assumptions [see shoyama et al. ( ) for details]. the grids which were intended to hold a population of only - people and be covered by the mnc were concerned to face possible shortages in labor required to maintain mnc. in the compact scenario, the number of such grids was larger than those of other scenarios and resulted in nearly , grids. in the dispersed scenario, there were a greater number of grids covered by mnc with populations of - people, compared to either the compact scenario or bau. as a nation-wide trend, the risk of shortage in labor for the management of natural capitals was deemed higher in the compact scenario compared with the dispersed scenario. an example of the spatial results of overlay analysis is shown here, with a focus on ishikawa prefecture. the overlaid results for natural capital-based scenarios are provided in this section (fig. ) , and the results of produced capitalbased scenarios are provided in online appendix . the maps in fig. show the spatial distribution of land cover types, and the depopulated grids (black dots) and highly aging grids (red and pink dots) covered by mnc. the number of grids with red dots increased in both the compact and fig. the number of grids covered by mnc by population density (nation-wide) dispersed scenarios, but the increment was more dramatic in the compact scenario (third row of fig. ). in the compact scenario, almost all the grids covered by mnc in the noto area (the location is shown in fig. ) were expected to experience serious depopulation and aging. in addition, the different scenarios revealed differences in type of mnc that would be expected to face higher levels of depopulation and aging. for both scenarios, plantation forest was a major mnc dotted by red and pink. however, in the compact scenario, many of the grids covered by paddy field in also face aging, such as around the reclaimed land of ouchigata (shown as a red circle in fig. , noto digital archive corporation). natural capital-based scenarios for the lulc map assumed that naturally produced rice would be preferred and larger areas of paddy field would not be abandoned compared to bau ). ouchigata reclaimed land was also projected to be maintained as paddy fields, but in the compact scenario, more than half of the residents of this area were projected to be over in . this was due to the expected outflow of younger people to the mid-scale regional urban areas, such as to kanazawa city from hakui city or nanao city which ouchigata reclaimed land belongs. the aim of this research was to develop a projection model of population distribution that expressed multi-level migration and assumed a depopulation trend. the model was built integrating cohort-component method with municipal resolution and a gravity model in grid resolution. this research is methodologically significant in three ways. first, this projection model is capable of expressing all four levels of migration (inter-regional, inter-prefectural, inter-municipal, and intra-municipal) that cause depopulation (matanle ) . this is achieved by combining municipal resolution projections to reproduce migration beyond prefectural and sub-national block boundaries, and the grid resolution model. given previous research in japan (see "modeling future population distribution"), this is a significant advance, as the model enables a realistic and complex projection of population distribution for countries experiencing depopulation. moreover, the model expresses population increments and decrements for medium-sized municipalities and grids with medium population densities for each scenario (fig. ) . due to the decrease in pressure to develop land that accompanies population decline, "selective national land utilization" is advocated in japan (mlit ) . this involves combining different development fig. summarized results of overlaying analysis focusing on ishikawa prefecture strategies according to municipal or area characteristics, such as compact city strategies in more populated and accessible areas, and rewilding strategies (gross ) in highly depopulated and aging areas. to select the most appropriate strategy, future dynamic changes of municipalities and grids with medium-scale population density must be projected and considered. this model can provide outcomes which contribute to "selective" national land development design and local development strategies. second, by applying the cohort-component method, the model enables population projection by -year age group. this overcomes one of the limitations of matsui et al. ( ) in which the total population was projected based on pances scenarios. aging has as serious an impact on the socio-ecological system as depopulation, and spatial analysis of the degree of aging (fig. ) by age-specific projection is a novel and necessary approach to understanding current patterns of depopulation and aging. in addition, by adjusting parameters used for the cohort-component method, other alternative scenario analyses can be more easily conducted. due to highly uncertain future population development (gross ) , a greater variety of scenarios must be examined, including the multiple fertility and mortality sets assumed by ipss (ipss ) . this flexibility allows this projection model to expand scenario analysis and to apply analysis to other countries experiencing similar post-growth development pathways and eventual depopulation (eberstadt ; matanle ) . third, overlaying this analysis on future lulc maps is a valuable method for determining coherent socio-ecological systems policies (see "overlaying on the future land use map"). decline-oriented planning is characterized by a spatially selective approach, and a coherent and holistic approach that addresses all economic, social, and environmental issues is essential (daly and kitchin ) . in this research, overlay analysis spatially demonstrated how the consistency of land use as an environmental aspect and population as a social aspect can be realized. further scenario assessments of economic aspects are expected in the future research through the integration of related models, such as surquas (smart urban area relocation model for sustainable quality stock, togawa et al. ) or exss model (a regional input-output model, gomi et al. ) . as other future research agenda, additional projection of future land use harmonized with this study's projected population distribution is also significant. by utilizing the population-projection-assimilated predictive land use modeling (ppap-lm) approach applied by ohashi et al. ( ) , actual land use patterns affected by population dynamics can be projected in order to support more realistic policy-making. furthermore, in reference to previous research (e.g., matsui et al. ) , expanding the target of this projection model to the working population employed in industrial sectors related to natural capital management is also expected to support the development of feasible industrial policies. the study highlighted challenges and proposed necessary interventions to realize a sustainable socio-ecological system under the compact and dispersed population dispersion scenarios. the first potential problem of the compact scenario is that many municipalities are concerned about the loss of necessary daily services due to population decline. for example, the population size of a municipality should exceed to enable the placement probability of book stores or dental clinics to exceed % (mlit ). given the large number of municipalities with populations of less than among scenarios (fig. ) , enhancing the "networks" between municipalities at various levels is more significant in the compact scenario. in this manner, healthy and cultural lives in small municipalities can be maintained. in other words, inter-municipal cooperation, which is a characteristic of decline-oriented planning (daly and kitchin ) , is more significant in a compact society. "networks for a new era" (mlit ), such as advanced information and communications networks that enable remote medical care and education, must be promoted as part of the information and communications policy of japan (mic ). the second expected challenge under the compact scenario is the shortage of labor for the management of natural capitals. the overlay analysis of the grid resolution identified places where mnc should be maintained, such as paddy fields. under the nc scenario, the identified areas, such as the ouchigata reclaimed land, will face severe aging by (fig. ) . to sustain the paddy fields, which are significant wintering sites for migratory birds (noto digital archive corporation), external participants in activities designed to manage mncs are necessary. relevant policies have been formulated to promote such a "related population" (i.e., people who continuously have relationships with a specific region; naito et al. ) . the initiative to call for volunteer workers for agricultural activities from outside ishikawa prefecture is called "work stay at ishikawa" (ishikawa prefecture b). the national policy called "related population creation and expansion project (mic d)" aims to provide financial support for the local development of the creation of a related population. moreover, smart agricultural technologies (maff ) can be considered another essential solution to support limited labor. technologies that make activities to maintain mncs easier and more accessible for anyone, such as power-assisted suits, must be implemented under the nc scenario. "project for accelerating installation of smart agriculture (maff)" is expected to expand as a supportive policy for local efforts to install smart agricultural technologies. as opposed to not only the compact scenario but also bau, the dispersed scenario resulted in a larger population size in areas covered by the mnc (fig. ; less grids with less than people) compared to . in other words, the dispersed scenario cannot be achieved unless a new type of migration opposite of the current trend toward bau becomes a major trend. this challenge remains for the dispersed scenario. the argued major keys to increase the influx of younger migrants from metropolitan areas to small regional urban and rural areas are profitable and attractive employment and attractive living environment, where raising children is easy (cabinet office ). several measures are expected to create employment. for example, promoting the development of industries with a high affinity for localization, such as welfare, health care, interpersonal services, environmental sectors, culture, and agriculture is important. another measure is that financial support can be given for migrants who contribute to activities for local development, such as the "local vitalization cooperator," which has been in operation since (mic e, hiroi ). moreover, advanced measures that overcome the challenges of existing childcare and education support are necessary. as an alternative, a variety of childcare services can be promoted for migrants without relatives in the neighborhood (kukimoto ) . moreover, development of rural communities with social inclusiveness throughout cultural opportunities can be expected as an effective measure (hirata ) . the covid- pandemic in has led to increased awareness of the risks of living in urban areas with large populations, whereas the advantages of a regional dispersed society have been discussed more seriously and widely (moe ; national governors' association ). the rapid spread of teleworking and increased number of metropolitan residents interested in migrating to rural areas have also been reported as part of the impacts of covid- (cabinet office ; nippon institute for research advancement ). this movement can become an opportunity to accelerate the formation of a dispersed scenario. further projection of population distribution reflecting new dispersed settlement styles and industrial structures corresponding to coexistence with covid- is required in future studies. moreover, this study contributes to providing detailed possibilities for the mixing of multiple scenarios. as murayama ( ) argues, there is no universal approach to land use planning for a depopulating and aging society and, in reality, a one-size-fits-all scenario cannot be rolled out across japan. local municipalities and communities need to plan the most appropriate direction for future growth given their unique local characteristics and circumstances and referring to the four quadrants of the pances scenario. the result of the study can support such initiatives through the spatial description of the different potential challenges related to population distribution under different scenarios. in addition, given that many solutions for sustainability are a combination of both nature-based and human/industrial elements (schaubroeck ) , future strategies in any one area must also combine natural capital and produced capitalbased scenarios. one example of this is that smart agriculture technologies are recommended for ouchigata reclaimed land to optimize a natural capital-based compact society. this exploratory analysis can lead the way to actual future strategy design by mixing pances scenario assumptions. this study developed a projection model of future population distribution under current japanese depopulation trends and applied it to a series of scenario analyses that assumed population compactification and dispersion at both national and prefecture scales. the resulting population distribution projection for reveals spatial changes to population density, age structure, and the appearance of zero population areas. by overlaying these data on future lulc maps, population distribution maps can identify locations and types of mnc that will face labor shortages. based on the results, the study proposes several political measures to overcome the challenges of the compact scenario, such as promotion of information and communications networks which enhance inter-municipal cooperation and support to invite external participants to aid in natural capital management. for the realization of the dispersed scenario, promoting industries with a high affinity for localization and developing attractive rural communities for young migrants through diversified childcare services and cultural opportunities are necessary. in conclusion, this study has developed a useful tool to support spatially explicit and practical planning for the management of natural capital at multiple scales to promote sustainable socio-ecological systems under depopulation and aging trends. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. development of formulation method for 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practising the scenario axes technique measuring and assessing urban sprawl: what are the remaining options for future settlement development in switzerland for ? key: cord- -lnr w ek authors: rothman, s; gunturu, s; korenis, p title: the mental health impact of the covid- epidemic on immigrants and racial and ethnic minorities date: - - journal: qjm doi: . /qjmed/hcaa sha: doc_id: cord_uid: lnr w ek nan severe acute respiratory syndrome-coronavirus (sars-cov ) the virus causing cov disease- (covid- ) has had a profound impact on humanity, stretching far past health, affecting commodity pricing, the global economy and employment. according to the world health organization, other respiratory viruses have emerged that have also impacted public health, however, not to this magnitude. these other instances include sars-cov in - , h n in and the middle east respiratory syndrome-cov which was first identified in in saudi arabia. the current iteration of the virus was first described in wuhan, a metropolitan area in the hubei province of china. although cases were first described in december , the disease did not reach to the level of a pandemic until march . as of may , there are over million confirmed cases of the virus with deaths spanning countries. in the usa, there have been over . million cases with almost deaths. the largest number of cases within the usa have been seen in new york where in the month of may there have been over confirmed tests daily, bringing the total number of cases above spanning across different counties within the state. new york city has been the focal point of the virus, with hospitals running out of beds, ventilators and even basic medications. within new york city and the entire country, the impact of the virus has not affected everyone equally. there are those that are able to work from home, while others that are considered essential or front-line workers have continued to go to work each day. these people have been doing so, often with inadequate personal protective equipment, or insufficient knowledge about the disease, as treatments and recommendations are changing so rapidly. a number of factors have been identified when considering the high volume of cases seen within new york city. additionally, these same factors need to be examined when identifying which types of patient populations are being infected and having worse medical outcomes. old age, obesity, male sex and diabetes have all been linked with worse covid- outcomes. worse outcomes have also been found in african american populations, latino, american indian, alaska native and pacific islanders. disparities exist when looking at all disease; however, this pandemic has once again brought issues of inequality and resource scarcity to the forefront. although this pandemic did not cause these inequalities, the rate at which poor, immigrant and minority populations are being affected cannot be ignored and should not be understated. disease spread has been tracked by the cdc and geographic differences can be viewed through the lens of epidemiologic and population-level factors which include: the timing of covid- introductions, population density, age distribution and prevalence of underlying medical conditions among covid- patients, the timing and extent of community mitigation measures, diagnostic testing capacity and finally, public health reporting practices. in new york city, specifically in the bronx where it is estimated that % of individuals live below poverty level and the population is composed mainly of hispanics and african americans who may have a number of psychosocial issues including: poverty, homelessness, issues with access to health care, education and immigration concerns. additionally, this community, when compared with the rest of new york state specifically, has pre-existing medical comorbidities such as diabetes, hypertension, smoking and obesity at a significantly higher rate. new york city has reported greater age adjusted mortality secondary to covid- among african americans and latinos compared with white residents. two of the most common theories for the disproportionate burden of disease between racial groups include the differences in chronic disease conditions and living conditions and ability to engage in social distancing. as previously mentioned, comorbid conditions already affecting morbidity and mortality can lead to worse outcome from the novel cov; however, it should be noted that while racial minorities suffer more frequently from many of these chronic conditions (hypertension, diabetes mello type type and hyperlipidemi) copd and chronic lower respiratory disease are not some of them. the second factor is these poorer minority groups are more likely to be living in crowded, urban environments and be employed in public-facing occupations that have been deemed 'essential' whereby social distancing has been rendered more difficult or even impossible. many immigrants, including those that are undocumented have no access to primary care doctors, so they utilize the emergency room (er) as the only source of medical treatment. during the covid- pandemic, many of them have been without medical care due to fears of contracting the disease in that setting, whereas others could be unnecessarily exposed while seeking vital care from their only option. this same population has a high percentage of people that work in the service industry and are disproportionally affected by the economic ramifications of staying at home and social distancing. many of these workers are young and healthy, however diabetes affects % of the latino population and this medical comorbidity is a significant risk factor for severe covid- disease course. unfortunately, in addition to the increased medical problems these communities are experiencing, there is also an increase in the percentage of the population that suffers with severe and persistent mental illness as well as substance use. these patients also have a number of uncontrolled medical comorbidities and on average die - years earlier than the general population. covid- has impacted this population disproportionately with regards to their medical and psychiatric issues which put them at risk for psychiatric decompensation and would benefit from further review and data collection. although there has been a national increase since the onset of the pandemic on the negative impact on mental healthrelated issues, it seems that the community in the bronx is at risk to be disproportionately impacted by this. there will be an increased risk for psychiatric decompensation in this community that is already a high utilizer for services provided by the office of mental health. many patients here suffer from underlying mental health issues with comorbid substance abuse. one of the recommended strategies to prevent the spread of cov is social distancing. this includes separating and isolating oneself from their loved ones. this can exacerbate feelings in many mental health populations including anxiety, depression, ptsd. paranoid ideation and other psychotic symptoms can increase for people who suffer with schizophrenia and cases of first break have been reported with covid- weaving itself into the delusional and paranoid thinking. tobacco smoking remains a main cause of preventable death in the usa with deaths annually, and an approximate population of million adults currently smoking. it is a main risk factor for cardiovascular disease and respiratory disease, both of which have been associated with worse covid- outcomes. although patients have a wide variety of reasons for smoking, stress/tension relief, alleviation of depressed mood and sleeping problems are some of the common reasons. many of these symptoms are likely exacerbated due to covid- and its associated effects, related news coverage and economic hardships, making smokers more at risk to detrimental effects and outcomes. alcohol is another substance where use and misuse has stress as a prominent risk factor, allowing for these months since the covid- crisis to potentially cause a public health crisis. the misuse of this substance is another one of the leading causes of preventable mortality worldwide, with million deaths annually. mitigation efforts to stop the spread of the virus include social distancing which leads to increased isolation. long-term social isolation has a negative effect of stress, at least in non-human animals; however, the effects on the human population in chronic isolation have not yet been studied with respect to health and wellbeing. with increased stress leading to increased alcohol consumption, the problem could escalate further, especially when many clinics, rehabilitation centers and detoxification programs have either had to limit their services or close temporarily during the height of the crisis. additionally, a critical modality employed in these programs is group therapy and this was often done in person. given the mandatory social distancing requirements, this primary method of treatment could not be executed in its normal fashion. this could lead to otherwise medically stable patients having to endanger themselves with er visits, potentially exposing themselves to the virus. isolation, social distancing and the negative emotions that come with these practices can affect everyone, but in the mental health population including those who abuse substances anxiety, fear, irritability, boredom can all be triggers for relapsing. withdrawal symptoms can also be so severe for patients who aren't able to get their drug of choice or be maintained in a maintenance program, which could cause patients to make risky decisions and endanger themselves and anyone who they cohabitate with. the homeless population is a group that includes those who are immigrants, those with mental illness and substance abuse issues. they often are forced to stay in shelters where the six feet of separation is not possible. the crowded areas they frequent and migrant habits in the day time make them not only high risk to contract the virus but to spread amongst themselves but also to hospitals throughout an urban environment. both tobacco and alcohol have been known to worsen flu symptoms, so there is a working assumption that this would be true for the novel cov as well. substance abuse has been increasing in the elderly population, who are already suffering from worse disease outcomes due to other medical comorbidities. substance abuse with opioids that can cause respiratory depression is also assumed to lead to worse outcomes, even for those patients who otherwise might have had a mild disease outcome. the ramifications of covid- are still growing each day, and governments are wrestling with the challenges of keeping the population healthy versus providing relief to the struggling economy. this reality begs for answers regarding what can be done to mitigate this type of disaster in the future. telehealth is surely a modality that has significant potential, and clinics and hospitals must need to have a better level of disaster preparedness going forward. these measures should not just be for a health crisis such as an infectious disease pandemic, but should include planning for natural disasters, terrorism and other wide scale events that could affect patients' health and livelihood alike. access to care for patients with different levels of insurance, transit capabilities and money all need to be taken into account, otherwise many of the lives lost in this crisis could be in vain. lessons learned from the epidemic include having a contingency plan for staff shortages, especially doctors, nursing staff and frontline hospital workers who can become infected with the very disease they are trying to fight. a back-up system needs to be available, and the field of telehealth, including telepsychiatry could provide service to patients while minimizing the exposure of clinical staff. telehealth would also help patients not having to make dangerous and unnecessary trips out of the home for outpatient visits. also, many clinics are physically attached to hospitals which have the highest concentration of sick and infectious people putting clinic patients at an unneeded risk. this problem is more so relevant for minority and immigrant populations who are less likely to have their own vehicle and rely more on the public transit system. immigrant populations already living in fear of deportation had difficulties receiving medical care prior to covid- . although the federal government announced that aliens would be able to seek preventative services and necessary medical treatment during this pandemic without fear of deportation, this might be difficult for many of them to believe given past government action. additionally, while the affordable care act allows for er visits for undocumented immigrants, many of them cannot access care from a primary care provider. now this population would be forced to seek care in the emergency setting, despite that being a high risk place to contract covid- . to help facilitate the ease into telehealth, non-health insurance portability accountability act (hipaa) compliant platforms such as skype and facetime have temporarily become an allowed option during the pandemic. for some patients, platforms like these are all they would want to use for telehealth visits as they might not have the resources for more expensive applications or even the type of smart phone or computer to utilize more expensive options. free applications help to level the playing field for patients with poor socioeconomic status, who would also save money on public transit by not having to travel to appointments that did not necessarily require an inperson evaluation. many clinics that cater to this group of patients often are resource poor and might not even have access to other platforms for telehealth, so if this emergency legislation to waive hipaa could lead to free applications becoming hipaa compliant or to changing the law in general, it would allow for this marginalized patient group to have better access to this modality of treatment. although the notion of telehealth certainly holds promise for medical care in the future, psychiatric patients would be a group of patients that would benefit from this modality in times of crisis where increased stressors are apparent and could even lead people with no psychiatric history to precipitate into crisis. in italy, where many day facilities were closed and residential facilities limited the movement of their patients, e-health services played a vital role in patient care. the italian department of mental health also noted the increased need for services when family are now spending more time face to face in close quarters which could lead to an increase in conflict. a strategy they also noted for planning for future pandemics or natural disasters would be to have medical professionals disseminate accurate and helpful information to the general public. in this digital age where a plethora of information sources are available, but the validity and accuracy of the sources are hard to verify, doctors should be at the forefront of the dialog, educating the public on accurate and peer reviewed scientific evidence. in conclusion, different areas of the country have been affected by the virus to differently due to many factors including how quickly social distancing was enacted, population density and testing capabilities. within these areas, it has also become apparent that certain minority and ethnic groups have been affected differently, as have patients with certain underlying conditions whether they be mental health-related or other chronic diseases. certain disparities and correlations with chronic disease were not caused by this pandemic, but were highlighted and brought to the forefront, receiving national attention. moving forward, along with fighting this disease, steps need to be taken to help stop a disease like this from impacting society to this level. it is unclear what a return to normalcy will look like, as is the timeline, and if the 'new normal' will be a permanent change. what should be a permanent change is having medical professionals play a larger role in the dissemination of accurate medical information, trying to lessen the panic that is accompanied with sensationalism in the news. furthermore, systems should be in place for patients to receive medication and telehealth services, to keep healthy and stable people from decompensating. immigrants including those that are undocumented are often already in a difficult predicament regarding access to medical care, and permanent changes should be in place to help them access care in the appropriate setting, without putting undue strain on ers. emergency settings are already overburdened, which in any time of crisis is significantly worsened. in uncertain times, anyone in the population is susceptible to stress, and some will turn to illicit substances for comfort. individuals already battling substance abuse and mental illness will therefore be more at risk of relapse, and services need to be in place for them as well. there needs to be an appropriate regimen for society's reentry, what remains to be seen is if in the process of doing so, chronic deep-seeded disparities can also be mitigated. conflict of interest. none declared. undocumented u.s. immigrants and covid- hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease -covid-net, states pé rez-stable ej. covid- and racial/ethnic disparities implications of changing public charge immigration rules for children who need medical care centers for disease control and prevention. smoking and tobacco use: data and statistics smoking and mental illness among adults in the united states. cbhsq report world health organization effect of social isolation on stress-related behavioural and neuroendocrine state in the rat the covid- pandemic and its impact on substance use: implications for prevention and treatment martín v; the ciberesp cases and controls in pandemic influenza working group. smoking may increase the risk of influenza hospitalization and reduce influenza vaccine effectiveness in the elderly substance abuse among older adults challenges and priorities in responding to covid- in inpatient psychiatry risk management amid a global pandemic mental health in the coronavirus disease emergency-the italian response key: cord- -fb rtmx authors: joseph, maxwell b.; mihaljevic, joseph r.; arellano, ana lisette; kueneman, jordan g.; preston, daniel l.; cross, paul c.; johnson, pieter t. j. title: taming wildlife disease: bridging the gap between science and management date: - - journal: j appl ecol doi: . / - . sha: doc_id: cord_uid: fb rtmx . parasites and pathogens of wildlife can threaten biodiversity, infect humans and domestic animals, and cause significant economic losses, providing incentives to manage wildlife diseases. recent insights from disease ecology have helped transform our understanding of infectious disease dynamics and yielded new strategies to better manage wildlife diseases. simultaneously, wildlife disease management (wdm) presents opportunities for large‐scale empirical tests of disease ecology theory in diverse natural systems. . to assess whether the potential complementarity between wdm and disease ecology theory has been realized, we evaluate the extent to which specific concepts in disease ecology theory have been explicitly applied in peer‐reviewed wdm literature. . while only half of wdm articles published in the past decade incorporated disease ecology theory, theory has been incorporated with increasing frequency over the past years. contrary to expectations, articles authored by academics were no more likely to apply disease ecology theory, but articles that explain unsuccessful management often do so in terms of theory. . some theoretical concepts such as density‐dependent transmission have been commonly applied, whereas emerging concepts such as pathogen evolutionary responses to management, biodiversity–disease relationships and within‐host parasite interactions have not yet been fully integrated as management considerations. . synthesis and applications. theory‐based disease management can meet the needs of both academics and managers by testing disease ecology theory and improving disease interventions. theoretical concepts that have received limited attention to date in wildlife disease management could provide a basis for improving management and advancing disease ecology in the future. population density decreased due to disease, contact rates would become too low for transmission to continue; thus, pathogens would be extirpated before host populations (anderson & may ) . however, disease-induced declines and extinctions of wildlife resulting from small population sizes, reservoir hosts, host switching and heterogeneity in contact rates, susceptibility and transmission within and among populations have forced a re-evaluation of this perspective (de castro & bolker ) . for example, when contact rates among individuals do not depend on host density, pathogens are more likely to drive populations to extinction because transmission continues as host populations are reduced, as seen with tasmanian devil sarcophilus harrisii (boitard ) facial tumour disease where transmission appears to be related to mating behaviours (mccallum ) . white nose syndrome in bats also seems to be more likely to cause extinctions owing to social behaviours in which hosts cluster in hibernacula, reducing the correlation between contact rates and population densities (langwig et al. ) . in recent decades, wildlife disease management (wdm) has been increasingly used to conserve threatened wildlife populations (deem, karesh & weisman ) . for example, wdm has controlled outbreaks of feline leukaemia in critically endangered iberian lynxes lynx pardinus (temminck ) and rabies in endangered ethiopian wolves canis simensis (r€ uppell ), both of which are associated with domestic animal disease reservoirs (haydon et al. ; l opez et al. ). despite the wealth of empirical wdm research, management outcomes can be difficult to predict because system-specific information is lacking for novel pathogens and many theoretical concepts in disease ecology (see table for a subset) have not been widely tested in the field, leading to uncertainty in their generality. this is unlike other environmental management disciplines such as fisheries ecology, which has effectively used theoretical models to predict yields, manage harvest timing and limits and design reserves (e.g. gerber et al. ) . indeed, theoretical applications in fisheries ecology have also produced insights into density-dependent population dynamics, metapopulation theory and the evolution of life-history table . selected theoretical concepts in disease ecology: theoretical concepts in disease ecology theory that apply to wildlife disease management, some direct management implications and a theoretical reference for each concept theoretical concepts management applications selected references host population regulation by disease disease reductions may increase host abundance and/or survival anderson & may ( ) trade-offs between transmission and virulence artificial stocking may increase virulence, and culling may reduce or increase virulence depending on pathogen life-history, culling selectivity and transmission dynamics frank ( ) seasonal drivers of disease emergence and dynamics intervention timing and frequency matters; control efforts can target transmission peaks altizer et al. ( ) pathogen interactions within hosts managing one pathogen alters the transmission and virulence of other pathogens fenton ( ) multi-host species disease dynamics reservoir hosts can drive the extinction of alternate hosts; rates of interspecific transmission may be inferred by managing one host species; management may need to target multiple host species dobson & foufopoulos ( ) spread of disease in spatially structured hosts corridor vaccination can reduce disease in metapopulations; movement controls are unlikely to work for chronic infections keeling & eames ( ) transmission increases with host density host density reductions may reduce disease transmission, and density thresholds for disease persistence may exist anderson & may ( ) transmission increases with disease prevalence independent of host density transmission associated with sexual interactions is more likely to cause host extinction, and non-selective culling may not reduce transmission getz & pickering ( ) predation as a regulator of host population and disease predator conservation may reduce disease in prey populations packer et al. ( ) community composition, diversity and disease risk biodiversity loss and community disassembly may increase disease as predators and less-competent hosts are extirpated, depending on community composition and transmission dynamics keesing, holt & ostfeld ( ) environmental reservoirs and indirect transmission duration of disease control must scale with the environmental persistence; host extinction is more likely joh et al. ( ) individual-level variation and superspreading heterogeneity in individual resistance and infectiousness within a host population can lead to 'superspreaders' that account for a large portion of transmission; management can target superspreaders lloyd-smith et al. ( ) strategies (frank & leggett ) . in this review, we assess the extent to which a similar union between theory and practice has been achieved in wdm. we use a quantitative, case-based approach to provide a critical retrospective of wdm over the last four decades to: (i) quantify how frequently specific theoretical concepts from disease ecology have been applied in the literature, (ii) identify prevailing management objectives, groups and reported outcomes and (iii) assess taxonomic biases in wdm literature. we then present methodological and conceptual opportunities to facilitate the newly emerging synthesis of disease ecology and management, drawing from environmental management and biomedicine to outline steps towards more cost-effective, efficacious and informative wdm. this synthesis aims to facilitate the development of a more predictive framework for disease interventions while simultaneously building empirical support for understanding of disease processes across systems. we compiled wdm case studies using a systematic, twostep search process with specific criteria for inclusion in our review. in the first stage, we searched titles and abstracts of records included in isi web of science using specific terms [(wild*) and (disease* or infect* or pathogen* or parasit*) and (manage* or conserv*)] to capture breadth in published wdm records. additionally, we searched for case studies in grey literature using the following online resources: national wildlife health center, wildpro, national biological information infrastructure wildlife disease information node, u.s. government printing office and the u. s. fish and wildlife service. no case studies identified in the grey literature met our criteria that were independent of cases identified in the scientific literature. case studies were also identified using previous review papers and books (lafferty & gerber ; wobeser ; hudson et al. ; wobeser ; ostfeld, keesing & eviner ) . we conducted a follow-up search with isi web of knowledge to capture subject depth for each managed disease or pathogen identified in the first step, using a search string that included all pathogen and disease names along with terms related to management interventions: (e.g. (rabi* or lyssavir*) and (vaccin* or treat* or manag* or control* or preval* or incidence or cull*) and (wild* or free-ranging or free ranging). the initial web of science search returned articles dating back to , but our disease-specific search strings often returned results dating back to the s or earlier. historical accounts of wdm are probably under-represented in the literature available online, and those returned by our search strings were often less readily accessible than recently published articles. as a result, the cases reviewed here primarily represent recently published cases of wdm. the publication dates of included cases range from to , and % of the cases included in our review were published after . for each article that met our criteria, we recorded (i) pathogen and host characteristics, (ii) management motivations, strategies and outcomes and (iii) whether and how disease ecology theory was incorporated in each article that satisfied our criteria. we only included cases that provided quantitative data on disease in a population or area (number of cases, seroprevalence, prevalence, incidence, etc.). when multiple records were encountered for a single management event, we used the most recent record (as of spring ). cases that only described disease management in humans, livestock or plants were excluded. finally, we only included studies that described management of diseases in populations (operationally defined as groups of > individual) of free-ranging wildlife. incorporation of disease ecology theory was defined broadly as the explicit use or discussion of theoretical concepts relating to transmission dynamics, host population regulation by disease, pathogen evolution, host or pathogen community effects on transmission, spatial heterogeneity in disease dynamics, life stage-or age-specific disease dynamics, endemic vs. epidemic disease states and herd immunity (see table for a list of specific concepts used to define theory in the literature search). four broad management objectives were identified, including conservation of a host species, prevention of disease transmission to humans, prevention of disease transmission to livestock and basic research. studies falling into our basic research category were usually an attempt to better understand the system, determine the extent of the disease problem or provide insight into future management opportunities. to investigate differences in theory application and objectives among managing groups, we also classified author affiliations for each paper as academic, governmental, private or some combination thereof. university or university laboratory affiliations were considered academic, and we used the same criteria for governmental and private affiliation. mixed author affiliations (e.g. academic and governmental) were recorded for individual authors and for papers with multiple authors with different affiliations. we characterized management outcomes by recording whether the disease was eradicated, and if not, whether there were changes in the prevalence, incidence or intensity of disease. ideally, these changes could be quantified and compared across disease systems, but in many cases, inconsistent reporting of results and a lack of pre-management or control data complicate meaningful quantitative comparisons of effect sizes across studies. finally, we considered whether the original management objective was attained using the following categories: 'apparent success', meaning that there was no unmanaged control population or area to compare to the treated area; 'partial success', meaning that at least some of the management objectives were reported as fulfilled; and 'success,' for cases that had controls and reported fulfilment of all management objectives. while management outcomes are rarely clear-cut in this practice, this simplified classification system facilitated coarse comparisons across disease systems and among management studies with variable monitoring time-scales. in total, scientific articles among the identified from the search strings satisfied our criteria (see appendix s and table s in supporting information). many ( %) cases consisted of collaborations between government agencies and academic researchers (fig. ) . conservation motivated % of management that involved private groups, whereas basic research was only conducted when academics were involved. overall, host conservation was the most common objective ( % of cases), while reducing disease risk to humans and domestic animals were the next most common objectives ( % and % of cases, respectively; fig. ). disease ecology theory as defined above has only recently been incorporated consistently into wdm literature (fig. a) . some theoretical concepts such as density dependence in transmission were frequently applied, while others such as pathogen evolution and the role of predators and biodiversity in regulating disease were not (fig. , table ). unexpectedly, papers authored by academics were not more likely to incorporate theory (fisher's exact test, p = Á ). management outcomes were related to theory incorporation (fisher's exact test, p = Á ). the three papers that reported disease increases following intervention explained their results in terms of disease ecology theory, providing insights into transmission and optimal control strategies (e.g. cross et al. ; fig b) . however, there was no relationship between management objective attainment and theory incorporation (fisher's exact test, p = Á ). nevertheless, some counter-intuitive but successful management distribution of management outcomes according to whether disease ecology theory was incorporated. reductions and increases refer to changes in prevalence, incidence, infection intensity or diseaseinduced mortality; eradication refers to local rather than global eradication. programmes clearly benefited from theory. for example, control of classical swine fever in wild boar sus scrofa (linnaeus ), is often hampered by stage-dependent transmission dynamics. susceptible piglets are hard to target with baited vaccines and act as disease reservoirs. by allowing an epidemic to peak such that most adults are immune, then culling only piglets, swiss academics and governmental groups successfully eradicated the disease from a -km region near the italian border (schnyder et al. ) . reductions in prevalence, incidence or infection intensity were reported in % of cases, with vaccination and host treatment as the most commonly applied intervention strategies (fig. b) . ninety-four percentage of cases reported management in terrestrial systems, with % and % of cases reporting management in freshwater and marine systems, respectively. the majority ( %) of reported management efforts were directed towards mammals, with birds and fish representing % and % of cases, respectively. however, mammals are less speciose and less threatened by disease than amphibians (vi e, hilton-taylor & stuart ), for which we found no published wdm records. taxonomic bias could arise because vaccines and drugs are developed primarily to protect human, livestock or poultry health. relatively few cases ( %) reported a failure to meet management objectives, possibly due to negative publication bias. collectively, our analyses indicate that while academics and government agencies collaborate to manage wildlife diseases, collaborations do not necessarily lead to an integration of disease ecology theory with management. density-dependent transmission was often assumed to justify control efforts, but other theoretical concepts were rarely applied (fig. ). data quality issues and potential publication biases currently hinder the application of metaanalytical techniques for wdm, and there is a paucity of published records on non-mammalian management. overcoming challenges to theory-based management while collaboration alone may not necessarily lead to an integration of disease ecology theory and wdm, it should provide a starting point for such integration. academics and managers have unique needs, constraints and knowledge-seeking behaviour that challenge such collaborations. for instance, untreated control areas or pre-treatment data can be unavailable or even unethical in wdm, but are critical for experiments in disease ecology. while academics may design field experiments to test and refine theoretical models, managers need practical, effective and uncontroversial management strategies that succeed in particular systems. such strategies may not be easily identified in the literature from model systems, which managers may be unable to access. modelling wildlife disease systems requires decisions about model complexity. in our experience, theoreticians prefer simpler, more general models that may be applicable to many systems. these models are easier to parameterize and analyse, and the resulting papers are likely to have a wider academic audience. on the other hand, simple models are easily discarded by managers because they lack system-specific detail. this tension is likely to continue, but we recommend additional flexibility on both sides. in particular, managers should appreciate that the addition of modelling details that are only weakly supported by data may not lead to better predictions. meanwhile, theoreticians may develop general models that bear little resemblance to any biological system. furthermore, individuals may be most interested in a particular suite of theoretical concepts, but a narrow approach can impede management by ignoring the full range of phenomena relevant to producing desired management outcomes (driscoll & lindenmayer ) . thus, academics and managers are challenged to take a broad view that incorporates relevant theoretical concepts and an appropriate amount of biological realism, which may require collaboration among researchers with different areas of expertise (driscoll & lindenmayer ) . unfortunately, such large collaborative efforts may bring a loss of autonomy at odds with academic or governmental bureaucracy. a diverse body of literature addresses the gap between academics and environmental managers and provides examples of successful strategies for integration. for instance, international symposia have improved information transfer in invasion biology (shaw, wilson & richardson ) . social networking, joint appointments, interinstitutional sabbaticals, fellowships, concise reporting table , and their application in the literature was included in this review, showing that some concepts such as densitydependent transmission are well represented, while others were less frequently (or not at all) applied. of relevant science to managers and targeted calls for research proposals by managers can all help to foster cooperation (gibbons et al. ) . interdisciplinary working groups for particular management issues can ensure that the needs of multiple stakeholders are considered together when organizing such activities (gibbons et al. ) . groups such as the wildlife disease association and applied journals including the journal of wildlife diseases have encouraged interdisciplinary collaboration, and a broader recognition of the complementarity between disease ecology theory and wdm can provide the impetus for expanding interdisciplinary work in this important field. theory can help address unprecedented management challenges and can be refined in the process. disease outbreaks are often caused by novel pathogens or the appearance of known pathogens in new hosts. often, details of host-pathogen interactions are unknown. by combining limited information with general principles of disease ecology (table ) theory is often refined by evaluating competing hypotheses. therefore, adaptive management is one way to integrate theory and management, especially if multiple management hypotheses can be tested (holling ) . differentiation among competing hypotheses is synonymous with identifying optimal management in this framework. thus, monitoring the effects of disease interventions on prevalence, virulence and host vital rates can help to estimate model parameters including transmission and recovery rates and help in evaluating management outcomes. when agencies have limited flexibility in decisionmaking, thus precluding adaptive management, the best available theoretical and system-specific knowledge can at least produce a 'best guess' management strategy (gregory, ohlson & arvai ) . failed management is still valuable in this framework because outcomes can be compared to predictions from competing models of disease dynamics that can be selectively eliminated, as with tasmanian devil facial tumour disease (mcdonald-madden et al. ). this approach produces mechanistic insights that might be missed if management strategies are characterized simply as effective or ineffective based on management outcomes. if many groups apply adaptive management separately in similar systems without communicating, generalities that benefit management and disease ecology may remain elusive. systematic reviews, invaluable to biomedicine, can help establish which interventions are effective and explain heterogeneity in effectiveness with a standardized meta-analytic approach. guidelines for systematic reviews in environmental management exist, but have not been applied in wdm (sensu pullin & stewart ) . our metadata indicate that this may be due to a lack of data quality and quantity. simple recommendations to facilitate the production of data suitable in quality for systematic review include: (i) establishing unmanaged control areas and/or baseline data, (ii) achieving replication, (iii) reporting precision for estimates of model parameters, prevalence and effect size, (iv) publishing and mechanistically explaining failed management and (v) reporting the spatiotemporal extent of management. data quantity may be lacking because of publication biases and a lack of incentives for managers to publish when working independently. this latter issue is minor if collaborations involve academics, but even motivated scientists may have difficulty publishing if management has no effect. however, management failures are as important to report in the literature as successes for systematic reviews and meta-analyses. an evaluation of the applicability of a theoretical concept in a particular case will rely on comparisons of observed data with explicit predictions from theoretical models, which can often be derived through mathematical modelling. theoretical concepts can be explicitly built into systemspecific mathematical models to identify and evaluate management strategies, as exemplified in a modern wdm challenge: chronic wasting disease (cwd). in , the state of wisconsin began culling white-tailed deer odocoileus virginianus (zimmermann ) and lengthened the hunting season in an attempt to eradicate cwd. these efforts were mandated despite uncertainty over transmission dynamics, the environmental persistence of prions that cause cwd and the time of cwd arrival to the state (bartelt, pardee & thiede ) . five years later, prevalence was still slowly increasing (heisey et al. ) . as this epidemic has unfolded, several models have been used to describe the dynamics of cwd (gross & miller ; wasserberg et al. ; wild et al. ) . simple models of cwd do not tend to produce plausible results. purely density-dependent transmission models predict increases in prevalence that are too rapid, while frequencydependent transmission models predict rapid host extinction or epidemics that are very slow to develop (on the order of centuries). modelling indirect transmission via environmental contamination results in a wider range of outcomes and produces several patterns observed in the field including a slow disease progression with prevalences of over % and significant host population reduction without rapid extinction (almberg et al. ) . recent analyses did not provide much support for models with variable increases in transmission over models with variable starting prevalence, suggesting that host density effects may be relatively weak in this system (heisey et al. ) . taken together, these results suggest that managers would have to reduce deer densities to extremely low levels, probably for decades, at which point other stakeholders such as hunters may wonder whether it is worse to have a lower deer density due to disease impacts or disease control efforts. disease ecology theory is not a 'silver bullet' for solving management problems. indeed, some have pointed out that application of theory under certain circumstances can lead to poor management (driscoll & lindenmayer ) . misapplication of theory at an inappropriate scale, or in a system that does not meet necessary assumptions, could cause undesired consequences. for instance, an assumption of broad-scale culling as a disease management intervention is that pathogen transmissions scale positively with host population density. however, density-dependent changes in social behaviour can alter dispersal patterns that violate this assumption, increasing transmission, as seen with bovine tuberculosis (tb) in cattle and european badgers meles meles (linnaeus ) (woodroffe et al. ) . work in the badger-tb system has refined our understanding of the effects of culling on social animals. however, one could argue that if culling-induced dispersal had been discovered in another disease system, the unintended increase in tb transmission to cattle following badger culling might have been avoided. unfortunately, had this been the case, the applicability of the social perturbation-transmission increase phenomenon to the badger-tb system would have remained uncertain. this underscores the value of moving beyond a case studydominated paradigm, towards a rigorous and empirically verified contingency-based understanding of theory applicability to disease management. such a framework could test and refine theoretical concepts that have shown promise in model systems, but have been infrequently applied in the wdm literature (fig. ) . what are the future directions for wdm? recent advances in disease ecology based on co-infection provide new ways to reduce disease susceptibility and transmission. for example, in african buffalo syncerus caffer (sparrman ), gastrointestinal nematodes reduce individual resistance to mycobacterium tuberculosis, which causes bovine tb, because of cross-regulatory immune responses to micro-and macroparasites (ezenwa et al. ) . hence, deworming drugs may increase resistance to tb and improve tb vaccination efficacy, raising the possibility that tb could be managed indirectly through nematode control (elias, akuffo & britton ; ezenwa et al. ) . management involving immunological trade-offs could improve general understanding of immune-mediated parasite interactions. for instance, interventions aimed at helminth parasites, which accounted for % of cases in our review, are predicted to differentially affect microparasite transmission depending on recovery rates and virulence (ezenwa & jolles ) . these predictions could be evaluated opportunistically by monitoring non-target pathogens. similarly, management in systems with co-infecting parasites could be used to understand virulence evolution in response to changing co-infection dynamics (alizon & van baalen ) . there is increasing recognition that microbial symbiosis can play a role in host health. using mutualistic microbes to control disease, a technique known as probiotics therapy, has benefitted aquaculture, agriculture and human medicine. for example, addition of bacillus and pseudomonas bacteria controls pathogenic vibrio that infect prawns, salmon and crabs in aquaculture (irianto & austin ; panigrahi & azad ) . bifidobacterium and lactobacillus can ameliorate escherichia coli infection in pig farms (zani et al. ; shu, qu & gill ) . in humans, probiotics can treat diarrhoea caused by clostridium difficile infection and antibiotic therapy (mcfarland ; rohde, bartolini & jones ). probiotics may prove useful for wdm. frogs with certain skin bacteria may be less susceptible to population extirpation caused by chytridiomycosis, a fungal disease that implicated global amphibian declines (lam et al. ) . experimental augmentation of skin bacteria reduces mortality of susceptible amphibians in captivity, and field experiments are underway to determine whether probiotics can prevent extirpations in nature (harris et al. ; rex ) . probiotics can also reduce vector populations. for instance, laboratory-reared mosquitoes with a maternally heritable probiotic that disrupts dengue fever virus transmission can locally replace wild mosquito populations and reduce dengue fever risk (hoffmann et al. ) . the successful use of probiotics depends on an understanding of microbial ecology, especially with respect to long-term probiotic maintenance in a host or environment. risks associated with introducing non-native microbes may be ameliorated by isolating probiotic agents from native hosts. as data accumulate, it will be important to evaluate whether the risks of probiotics outweigh those associated with antibiotic treatment in terms of antibiotic or probiotic resistance and pathogen virulence evolution. finally, linking these within-host processes to among-host processes (e.g. microbial community structure and transmission) is an important frontier for wdm and disease ecology. optimal management strategies depend on the degree to which transmission is driven by host population density and the amount of individual and population heterogeneity in contact or transmission rates. host population size, aggregation patterns and contact rates can be altered through hunting, artificial feeding, predator and scavenger conservation, fertility control, culling, translocation of individuals, artificial stocking, movement barriers, etc. understanding the functional form of the relationships among host contacts, density and transmission in real systems is critical to predicting the impacts of such interventions. therefore, field manipulations will play a crucial role in refining our mechanistic understanding of disease transmission. optimal management strategies are not static; contact rates, host abundance and demography can change naturally over time, in response to disease and due to management. for example, group sizes and contact rates may remain constant for highly social species despite management-induced population reduction. reservoir hosts may increase disease risk for other species if infected individuals maintain high fitness via increased reproductive output (fecundity compensation, for example, schwanz ) . fertility control of such reservoir hosts may protect other species that are less tolerant to infection. lastly, if transmission peaks in a short time period, perhaps due to breeding or a pulsed influx of juveniles (altizer et al. ) , management may be applied optimally in a narrow time interval. brucellosis in the elk (cervus elaphus linnaeus ) populations of the greater yellowstone ecosystem of wyoming illustrates how management can capitalize on temporal transmission dynamics. every year, wildlife managers provide supplemental feed to elk at sites in the region. contrary to theoretical predictions, elk abundance at each feeding site is uncorrelated with brucellosis seroprevalence (cross et al. ), but locally, host contact rates correlate positively with elk density (creech et al. ) . these seemingly contradictory findings are explained by variation and interaction between transmission and host density over time, which suggests that brucellosis seroprevalence may be reduced by shortening the length of the feeding season in early spring when transmission is highest (maichak et al. ). this option is appealing because vaccination has had limited, if any, effect (cross et al. ) , and a testand-remove programme, although effective, is financially prohibitive to implement across a broad region. establishing contact networks for a variety of disease systems across a range of densities and over time will help to identify life-history traits, social structures and other species characteristics that predictably influence transmission. taken together, these population-level tools can advance general understanding of transmission dynamics and optimize the application of disease control strategies. community-level interactions including predation and competition can influence disease management outcomes. predation on hosts can increase or decrease disease prevalence and the likelihood of epidemics depending upon predator selectivity, as well as behavioural and demographic effects on host populations that influence transmission and disease susceptibility (packer et al. ; holt & roy ) . interspecific competition can also influence host background mortality and thus the net effect of disease in a population (bowers & turner ) . unintended consequences when managing predators or competitors may be of less concern if coupled with ongoing management such as predator restoration and invasive species control. interspecific transmission of generalist parasites is hard to quantify, but attempts to control generalist parasites in one host species can reveal the extent to which other hosts contribute to transmission. for example, tsao et al. ( ) vaccinated white-footed mice peromyscus leucopus (rafinesque ) in southern connecticut to reduce the prevalence of borrelia burgdorferi, the bacterium that causes lyme disease. based on the strains of b. burgdorferi found in ticks in vaccinated plots, and the relationships between mouse density and tick infection prevalence, the authors concluded that other host species contributed more to tick b. burgdorferi infections than previously thought. thus, vaccination would have to target multiple host species to be effective. contact prevention between wildlife and livestock also provides an opportunity to prevent disease spillover, and when linked with monitoring of both wildlife and domestic populations, can be used to estimate relative rates of within-and among-species transmission. novel management strategies may target ultimate causes of disease emergence once they have been identified. for instance, lyme disease risk in the north-eastern united states increases with habitat fragmentation, which leads to extirpations of (i) predators and competitors that limit white-footed mouse abundance and (ii) less-competent hosts for b. burgdorferi and ticks (ostfeld & logiudice ) . in this system, biodiversity conservation might be an option for proactive wdm. management interventions that recognize and target community-or ecosystem-level processes are rare, but in some cases may more directly address disease threats than focusing solely on individuals or populations. a black box? common wdm interventions have evolutionary consequences that remain largely unexplored. in contrast, a vast literature in the biomedical sciences describes the effects of vaccination on the evolution of human pathogens. generally, (i) some pathogens tend to evolve vaccine resistance, (ii) imperfect vaccines that confer partial immunity select for increased virulence, and (iii) live attenuated vaccines can revert to virulence if inadequately distributed (anderson, crombie & grenfell ; gandon & day ; mackinnon, gandon & read ) . together, these observations provide strong incentives for an 'all or nothing' approach to vaccine-laden bait distribution programmes, which may jeopardize long-term success if low-coverage field trials using vaccines of limited or unknown efficacy precede full distribution of an effective vaccine. selective culling (analogous to selective predation) whereby managers remove infected individuals from the population to prevent disease spread may also have unintended consequences. it can select for increased virulence, because there are relatively more susceptible hosts available for the pathogen, and pathogens must transmit to susceptible hosts faster to avoid being culled along with their hosts (choo, williams & day ) . in many cases, selective culls are based on serological tests that do not discriminate between recovered and infectious individuals. removal of recovered individuals may actually result in more explosive epidemics later on due to a reduction in herd immunity (ebinger et al. ) . experiments and genetic analyses of wildlife pathogens that are often treated by vaccination or culling could reveal the extent to which these concerns are realized. aside from developing new vaccines, these risks may be mitigated if management capitalizes on immune-mediated parasite interactions, employ probiotic approaches and consider population-and community-level management interventions. the use of multiple strategies (seen in % of our case studies) may provide one means with which to avoid problems such as antibiotic or vaccine resistance resulting from the overuse of any one strategy. a more complete integration of disease ecology with wdm can benefit both disciplines. management provides unique opportunities to test disease ecology theory while building system-specific understanding. by evaluating management outcomes in terms of theory, managers can better identify effective strategies even in the face of management failures. we have presented specific recommendations, methodological tools and conceptual approaches to achieve a stronger integration of theory and practice, which we hope will facilitate the development of a strong predictive framework for wdm. the generality of this framework is currently limited by the lack of theoretical and taxonomic breadth of coverage. however, these biases are beginning to be addressed, and disease ecology theory is being integrated with wdm with increasing frequency. by continuing to incorporate ecological and evolutionary ideas in the development and evaluation of management actions, disease ecology and wdm are likely to continue to advance towards a more unified body of theory and evidence. multiple infections, immune dynamics, and the evolution of virulence modeling routes of chronic wasting disease transmission: environmental prion persistence promotes deer population decline and extinction seasonality and the dynamics of infectious diseases the epidemiology of mumps 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individuals with anti-batrachochytrium dendrobatidis skin bacteria is associated with population persistence in the frog rana muscosa sociality, density-dependence and microclimates determine the persistence of populations suffering from a novel fungal disease, white-nose syndrome should we expect population thresholds for wildlife disease? management measures to control a feline leukemia virus outbreak in the endangered iberian lynx virulence evolution in response to vaccination: the case of malaria effects of management, behavior, and scavenging on risk of brucellosis transmission in elk of western wyoming disease and the dynamics of extinction active adaptive conservation of threatened species in the face of uncertainty meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of clostridium difficile disease infectious disease ecology: effects of ecosystems on disease and of disease on ecosystems community disassembly, biodiversity loss, and 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approach to preventing human infection: vaccinating wild mouse reservoirs intervenes in the lyme disease cycle wildlife in a changing world. an analysis of the iucn red list of threatened species host culling as an adaptive management tool for chronic wasting disease in white-tailed deer: a modelling study the role of predation in disease control: a comparison of selective and nonselective removal on prion disease dynamics in deer disease management strategies for wildlife. revue scientifique et technique de l'office international des epizooties disease in wild animals: investigation and management culling and cattle controls influence tuberculosis risk for badgers effect of probiotic cenbiot on the control of diarrhea and feed efficiency in pigs we thank y.p. springer, v.j. mckenzie, s.h. paull, s.a. orlofske, s. ellis, t.j. zelikova, the cu disease discussion group and the johnson lab for insightful comments. any use of trade, product or firm names is for descriptive purposes only and does not imply endorsement by the u.s. government. a.l.a., d.l.p., j.g.k., j.r.m. and m.b.j. were supported by the nsf graduate research fellowship program. p.c.c.'s work was supported by u.s.g.s. and the nsf/nih ecology of infectious disease program deb- , and some ideas stem from working groups sponsored by the nih/dhs-funded rapidd program. p.t.j.j. was supported by a fellowship from the david and lucile packard foundation and grants from the national science foundation (deb- , ) and the morris animal foundation. the authors have no conflict of interests with regard to this research or its funding. additional supporting information may be found in the online version of this article.appendix s . references for reviewed articles. table s . metadata from reviewed articles. key: cord- -wvf cpib authors: benatia, d.; godefroy, r.; lewis, j. title: estimating covid- prevalence in the united states: a sample selection model approach date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: wvf cpib background: public health efforts to determine population infection rates from coronavirus disease (covid- ) have been hampered by limitations in testing capabilities and the large shares of mild and asymptomatic cases. we developed a methodology that corrects observed positive test rates for non-random sampling to estimate population infection rates across u.s. states from march to april . methods we adapted a sample selection model that corrects for non-random testing to estimate population infection rates. the methodology compares how the observed positive case rate vary with changes in the size of the tested population, and applies this gradient to infer total population infection rates. model identification requires that variation in testing rates be uncorrelated with changes in underlying disease prevalence. to this end, we relied on data on day-to-day changes in completed tests across u.s. states for the period march to april , which were primarily influenced by immediate supply-side constraints. we used this methodology to construct predicted infection rates across each state over the sample period. we also assessed the sensitivity of the results to controls for state-specific daily trends in infection rates. results the median population infection rate over the period march to april was . % (iqr . . ). the three states with the highest prevalence over the sample period were new york ( . %), new jersey ( . %), and louisiana ( . %). estimates from models that control for state-specific daily trends in infection rates were virtually identical to the baseline findings. the estimates imply a nationwide average of population infections per diagnosed case. we found a negative bivariate relationship (corr. = - . ) between total per capita state testing and the ratio of population infections per diagnosed case. interpretation the effectiveness of the public health response to the coronavirus pandemic will depend on timely information on infection rates across different regions. with increasingly available high frequency data on covid- testing, our methodology could be used to estimate population infection rates for a range of countries and subnational districts. in the united states, we found widespread undiagnosed covid- infection. expansion of rapid diagnostic and serological testing will be critical in preventing recurrent unobserved community transmission and identifying the large numbers individuals who may have some level of viral immunity. public health efforts to determine population infection rates from coronavirus disease (covid - ) have been hampered by limitations in testing capabilities and the large shares of mild and asymptomatic cases. we developed a methodology that corrects observed positive test rates for non-random sampling to estimate population infection rates across u.s. states from march to april . we adapted a sample selection model that corrects for non-random testing to estimate population infection rates. the methodology compares how the observed positive case rate vary with changes in the size of the tested population, and applies this gradient to infer total population infection rates. model identification requires that variation in testing rates be uncorrelated with changes in underlying disease prevalence. to this end, we relied on data on day-to-day changes in completed tests across u.s. states for the period march to april , which were primarily influenced by immediate supply-side constraints. we used this methodology to construct predicted infection rates across each state over the sample period. we also assessed the sensitivity of the results to controls for state-specific daily trends in infection rates. the median population infection rate over the period march to april was . % (iqr . . ). the three states with the highest prevalence over the sample period were new york ( . %), new jersey ( . %), and louisiana ( . %). estimates from mod- els that control for state-specific daily trends in infection rates were virtually identical to the baseline findings. the estimates imply a nationwide average of population infections per diagnosed case. we found a negative bivariate relationship (corr. = - . ) between total per capita state testing and the ratio of population infections per diagnosed case. the effectiveness of the public health response to the coronavirus pandemic will depend on timely information on infection rates across different regions. with increasingly available high frequency data on covid- testing, our methodology could be used to estimate population infection rates for a range of countries and subnational districts. in the united states, we found widespread undiagnosed covid- infection. expansion of rapid diagnostic and serological testing will be critical in preventing recurrent unobserved community transmission and identifying the large numbers individuals who may have some level of viral immunity. social sciences and humanities research council. in december , several clusters of pneumonia cases were reported in the chinese city of wuhan. by early january, chinese scientists had isolated a novel coronavirus (sars-cov- ), later named coronavirus disease (covid- ) , for which a laboratory test was quickly developed. despite efforts at containment through travel . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint restrictions, the virus spread rapidly beyond mainland china. by april , more than . million cases had been reported in countries and regions. our understanding of the progression and severity of the outbreak has been limited by constraints on testing capabilities. in most countries, testing has been limited to a small fraction of the population. as a result, the number of confirmed positive cases may grossly understate the population infection rate, given the large numbers of mild and asymptomatic cases that may go untested [ ] [ ] [ ] [ ] [ ] . moreover, testing has often been targeted to specific subgroups, such as individuals who were symptomatic or who were previously exposed to the virus, whose infection probability differs from that in the overall population [ , ] . given this sample selection bias, it is impossible to infer overall disease prevalence from the share of positive cases among the tested individuals. a further challenge to our understanding of the spread of outbreak has been the wide variation in per capita testing across jurisdictions due to different protocols and testing capabilities. for example, as of april , south korea had conducted three times more tests than the united states on a per capita basis [ , ] . large differences in testing rates also exist at the subnational level. for example, per capita testing in the state of new york was nearly two times higher than in neighboring new jersey [ ] . because the severity of sample selection bias depends on the extent of testing, these disparities create large uncertainty regarding the relative disease prevalence across jurisdictions, and may contribute to the wide differences in estimated case fatality rates [ , ] . in this study, we implemented a procedure that corrects observed infection rates among tested individuals for non-random sampling to calculate population disease prevalence. a large body of empirical work in economics has been devoted to the problem of sample selection and researchers have developed estimation procedures to notable exceptions include the universal testing of passengers on the diamond princess cruise ship, and an ongoing population-based test project in iceland. correct for non-random sampling [ ] [ ] [ ] [ ] [ ] [ ] . our methodology builds on these insights to correct observed infection rates for non-random selection into covid- testing. our procedure compares how the observed infection rate varied as a larger share of the population was tested, and uses this gradient to infer disease prevalence in the overall population. because investments in testing capacity may respond endogenously to local disease conditions, however, model identification requires that we find a source of variation in testing rates covid- that is unrelated to the underlying population prevalence. to this end, we relied on high frequency day-to-day changes in completed tests across u.s. states, which were primarily driven by immediate supply-side limitations rather than the more gradual evolution of local disease prevalence. we used this procedure to correct for selection bias in observed infection rates to calculate population disease prevalence across u.s. states from march to april . to evaluate population disease prevalence, we developed a simple selection model for covid- testing and used the framework to link observed rates of positive tests to population disease prevalence. we considered a stable population, denoting a and b as the numbers of sick and healthy individuals, respectively. let p n denote the probability that a sick person is tested and q n the probability that a healthy person is tested, given a total number of tests, n. thus, we have: cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint and the number of positive tests is: this simple framework highlights how non-random testing will bias estimates of the population disease prevalence. using bayes' rule, we can write the relative probability of testing as the following: q n p n = p r(sick|n)/p r(healthy|n) p r(sick|tested, n)/p r(healthy|tested, n) , which is equal to one if tests are randomly allocated, p r(sick|tested, n) = p r(sick|n). when testing is targeted to individuals who are more likely to be sick, we have p r(sick|tested, n) > p r(sick|n) and p r(healthy|tested, n) < p r(healthy|n), so the ratio will fall between zero and one. in this scenario, the ratio of sick to healthy people in the sample, p n a q n b, will exceed the ratio in the overall population, a b. we specified the following functional form for the relative probability of testing: which is in [ , ] for −a − bn ≤ . the term e −a−bn > reflects the fact that testing has been targeted towards higher risk populations, with the intercept, −a, capturing the severity of selection bias when testing is limited. meanwhile, the coefficient b > identifies how selection bias decreases with n as the ratio q n /p n approaches one. intuitively, as testing expands, the sample will become more representative of the overall population, and the selection bias will diminish. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint combining both equations, we have: we used the fact that the ratio of negative to positive tests is much larger than one to make the following approximation: given a change in the number of tests conducted in a particular population, n to n , equation ( ) implies the following change in the share of positive tests: our empirical model was derived from equation ( ). we used information on testing across states i on day t to estimate the following equation: where n i,t is the number of tests on day t, s i,t is the share of positive tests, and pop i is the state population. the term u i,t is an error which we assumed to follow a gaussian distribution with mean zero and unknown variance. we restricted the model to a cubic approximation of the function in equation ( ), since higher order terms were found to be statistically insignificant. this approximation is supported by graphical evidence depicted below. we estimated equation ( ) by maximum likelihood. for model identification, we required that day-to-day changes in the number of tests be uncorrelated with the error term, u i,t . in practice, this assumption implies that daily changes in underlying population disease prevalence cannot be systematically related to day-to-day changes in testing. our identification assumption is supported by at least three pieces of evidence. first, severe constraints on state testing capacity have caused a significant backlog in cases, so that changes in the number of daily tests primarily reflects changes in local capacity rather than changes in demand for testing. second, because our analysis focuses on high frequency day-to-day changes in outcomes, there is limited scope for large evolution in underlying disease prevalence. finally, in robustness exercises, we augmented the basic model to include state fixed effects, thereby allowing for state-specific exponential growth in underlying disease prevalence from one day to the next. these additional controls did not alter the main empirical findings. to recover estimates of population infection rates,p i,t , in state i at date t, we combined the estimates from equation ( ) and set n = pop i according to the following equation:p we then used the delta-method to estimate the confidence interval forp i,t . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the analysis was based on daily information on total tests results (positive plus negative) and total positive test results across u.s. states for the period march to april . these data were obtained from the covid tracking project, a site that was launched by journalists from the atlantic to publish high-quality data on the outbreak in the united stated [ ] . the data were originally compiled primarily from state public health authorities, occasionally supplemented by information from news reporting, official press conferences, or message from officials released on facebook or twitter. we focused on the recent period to limit errors associated with previous changes in state reporting practices. we supplemented this information with data on total state population from the census [ ] . ( ), estimated across states for the period march to april . becauseβ is negative, the upward sloping pattern implies a negative relationship between daily changes in testing and the share of positive tests. a symptom of selection bias is that variables that have no structural relationship with the dependent variable may appear to be significant [ ] . thus, these patterns strongly suggest non-random testing, since daily changes in testing should be . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint unrelated to population disease prevalence except through a selection channel. table reports the results that adjust observed covid- case rates for nonrandom testing based on the procedure described in section . for reference, column ( ) reports the observed positive test rate on april , . columns ( ) and ( ) the average estimates are similar to the april estimates, albeit generally smaller in magnitude, suggesting continued spread of the disease in many states. in table , we examined the robustness of the main estimates. to begin, we estimated modified versions of equation ( ) that include state fixed effects. these models allow for an exponential trend in infection rates, thereby addressing concerns that underlying disease prevalence may evolve from one day to the next. we allowed each state to have its own specific intercept to capture the fact that the trends may differ depending on the local conditions. the results (reported in cols. and ) are virtually identical to the baseline estimates. moreover, the augmented model tends to produce more precise confidence intervals. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . we explored the sensitivity of the results to excluding days in which a large fraction of tests were positive. this specification addresses concerns that the functional form of the estimating equation may differ in settings in which the share of positive was large, due to the approximation in equation ( ). we restricted the sample to observations in which fewer than % of tests were positive, and re-estimated equation ( ) . table , cols. , , report the results. although the sample size is reduced, the predicted infection rates are similar in magnitude to the baseline estimates and have similar confidence intervals. in table , we explored the relationship between the number of diagnosed cases and total population covid- infections implied by our estimation procedure. we compared the average population infection rates from march to april to the total number of diagnosed cases by april . because many individuals may not seek testing until the onset of symptoms, the latter date was chosen to capture the virus's typical five day incubation period [ , ] . column ( ) reports the total diagnosed cases by april ; column ( ) reports the total number of covid- cases implied by the estimates reported in table (col. ); and column ( ) presents the ratio of total cases to diagnosed cases. the results reveal widespread undetected population infection. nationwide, we found that for every identified case there were total infections in the population. there were significant cross-state differences in these ratios. in new york, where more than two percent of the population had been tested, the ratio of total cases to positive diagnoses was . , the lowest in the nation. meanwhile, oklahoma had the highest ratio in the country ( . ) , and tested less than . percent of its population. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint response to geographic differences in pandemic severity. instead, the patterns suggest that states that expanded testing capacity more broadly were better able to track population prevalence. and population prevalence. the similarity between these two series is notable, given that our estimates were derived from an entirely different source of variation from the cumulative case counts. nevertheless, observed case counts do not perfectly predict overall population prevalence. for example, despite similar rates of reported positive tests, michigan had roughly twice as many per capita infections as rhode island. these differences can partly be explained by the fact that nearly two percent of the population in rhode island had been tested by april , whereas fewer than one percent had been tested in michigan. together, these findings suggest that differences in state-level policies towards covid- testing may mask important differences in underlying disease prevalence. the high proportion of asymptomatic and mild cases coupled with limitations in laboratory testing capacity has created large uncertainty regarding the extent of the covid- outbreak among the general population. as a result, key elements of virus' clinical and epidemiological characteristics remain poorly understood. this uncertainty has also created significant challenges to policymakers who must trade off the potential benefits from non-pharmaceutical interventions aimed at curbing local transmission against their substantial economic and social costs. a number of recent studies have sought to estimate covid- disease prevalence and mortality in the united states and internationally [ ] [ ] [ ] [ ] [ ] [ ] . one approach has . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . other research has relied on bayesian modelling to infer past disease prevalence from observed covid- deaths, and apply sir models to forecast current infection rates. this approach requires fewer assumptions regarding the underlying parameter values. nevertheless, because these models 'scale up' observed deaths to estimate population infections, small differences in the assumed case fatality will have substantial effects on the results. this poses a challenge for estimation, given that there is considerable uncertainty regarding the case fatality rate, which may vary widely across regions due to local demographics and environmental conditions [ ] [ ] [ ] [ ] [ ] . moreover, to the extent that there is significant undercounting in the number of covid- related deaths [ , ] , these estimates may fail to capture the full extent of population infection. in this paper, we developed a new methodology to estimate population disease prevalence when testing is non-random. our approach builds on a standard econometric technique that have been used to address sample selection bias in a variety of different settings. our estimation strategy offers several advantages over existing methods. first, the analysis has minimal data requirements. the three variables used for estimation -daily infections, daily number of tests, and total population -are widely reported across a large number of countries and subnational districts. second, the model identification is transparent and depends only on a simple exclusion restriction assumption that daily changes in the number of conducted tests must be uncorrelated with underlying changes in population disease prevalence. this assumption is likely to hold in many jurisdictions where constraints on capacity are a primary determinant of . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . we used this framework to estimate disease prevalence across u.s. states. we our findings are comparable to previous studies on u.s. population prevalence that find ratios of population infection to positive tests ranging from to by mid-march [ , ] . despite a dramatic expansions in testing capacity in the intervening weeks, the vast majority of covid- cases remain undetected. our results are comparable to recent estimates of population prevalence in a number of european countries [ ] . we found a nationwide . percent infection rate in early april, which is similar to the estimated prevalence in austria ( . %), denmark ( . %), and the united kingdom ( . %) as of march . meanwhile, germany's . % infection rate would rank in the lowest tercile of prevalence among u.s. states. the highest rates of infection in new york ( . %), new jersey ( . %), and louisiana ( . %) are still lower than the estimated rates in italy ( . %) and spain ( %). given the rapidly expanding availability of high frequency testing data at both the national and subnational level, in future research we plan to apply this methodology to compare infection rates across a broader spectrum of countries. there are several limitations to our study, which should be taken into account when interpreting the main findings. first, the estimation results depend on several functional form assumptions including a constant exponential growth rate in new infections and the specific functions governing how the number of available tests affect individual testing probability. as more data on testing become available, the increased sample sizes will allow future studies to impose weaker functional form assumptions through either semi-or non-parametric approaches. second, our analysis required an assump- . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint tion that the underlying sample selection process was similar across observations. to the extent that decisions regarding who to test, conditional on the number of available tests, diverged across states or changed within states over the sample period, our model may be misspecified. finally, our analysis depends on the quality of diagnostic testing, and systematic false negative test results may affect the population disease prevalence estimates [ ] [ ] [ ] . as countries continue to struggle against the ongoing coronavirus pandemic, informed policymaking will depend crucially on timely information on infection rates across different regions. randomized population-based testing can provide this information, however, given the constraints on supplies, this approach has largely been eschewed in favor of targeted testing towards high risk groups. in this paper, we developed a new approach to estimate population disease prevalence when testing is non-random. the estimation procedure is straightforward, has few data requirements, and can be used to estimate disease prevalence at various jurisdictional levels. contributions db, rg, and jl conceptualized the study, analyzed the data, and drafted and finalized the manuscript. all authors approved of the final version of the manuscript. we declare no competing interests. this study was supported by funding from the social sciences and humanities research council (grant: sshrc - - ). provided that the rates of misdiagnosis were unrelated to the number of tests, these errors will not bias the coefficient estimates, but may reduce precision through classical measurement error [ ] . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . notes: columns ( ) to ( ) report the estimates and heteroskedasticity robust % confidence intervals for population prevalence of covid- on april based on the methodology described in section . columns ( ) to ( ) report the the average estimates for population prevalence of covid- from march to april . columns ( ), ( ) and ( ) report results based on models that include state fixed effects. columns ( ), ( ) , and ( ) report results based on models that restrict the sample to observations for which the share of positive cases was less than . . in cases of incomplete testing data on april , population prevalence is reported for the closest day: * indicates prevalence on april , ** indicates prevalence on april , and *** indicates prevalence on march . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint epidemiological characteristics of pediatric patients with coronavirus disease in china sars-cov- infection in children evidence of sars-cov- infection in returning travelers from wuhan, china asymptomatic cases in a family cluster with sars-cov- infection. the lancet infectious disease presumed asymptomatic carrier transmission of covid- therapeutic and triage strategies for novel coronavirus disease in fever clinics centers for disease control and prevention: coronavirus (covid- the covid tracking project the many estimates of the covid- case fatality rate. the lancet infectious disease coronavirus covid- global cases the common structure of statistical models of truncation, sample selection and limited dependent variables and a simple estimator for such models the economics and econometrics of active labor market programs evaluation methods for non-experimental data nonparametric estimation of sample selection models. the review of economic studies two-step series estimation of sample selection models annual estimates of the resident population for the united states, regions, states early transmission dynamics in wuhan, china, of novel coronavirus -infected pneumonia the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application impacts of non-pharmaceutical interventions to reduce covid- mortality and healthcare demand. london: imperial college covid- response team estimating unobserved sars-cov- infections in the united states. medrxiv working paper substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov ) adjusting age-specific case fatality rates during the covid- epidemic in hubei, china estimating sars-cov- positive americans using deaths-only data estimation of sars-cov- mortality during the early stages of and epidemic: a modelling study in hubei, china and norther italy the effects of outdoor air pollution concentrations and lockdowns on covid- infections in wuhan and other provincial capitals in china exposure to air pollution and covid- mortality in the united states pollution, infectious disease, and mortality: evidence from the spanish influenza pandemic what explains cross-city variation in mortality during the influenza pandemic? evidence from u deaths in new york city are more than double the usual total doctors and nurses say more people are dying of covid- in the us than we know chest ct for typical -ncov pneumonia: relationship to negative rt-pcr testing correlation of chest ct and rt-pcr testing in coronavirus disease (covid- ) in china: a report on cases evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of -ncov infections. medrxiv working paper econometric analysis of cross section and panel data key: cord- - mldz authors: viana, mafalda; mancy, rebecca; biek, roman; cleaveland, sarah; cross, paul c.; lloyd-smith, james o.; haydon, daniel t. title: assembling evidence for identifying reservoirs of infection date: - - journal: trends ecol evol doi: . /j.tree. . . sha: doc_id: cord_uid: mldz many pathogens persist in multihost systems, making the identification of infection reservoirs crucial for devising effective interventions. here, we present a conceptual framework for classifying patterns of incidence and prevalence, and review recent scientific advances that allow us to study and manage reservoirs simultaneously. we argue that interventions can have a crucial role in enriching our mechanistic understanding of how reservoirs function and should be embedded as quasi-experimental studies in adaptive management frameworks. single approaches to the study of reservoirs are unlikely to generate conclusive insights whereas the formal integration of data and methodologies, involving interventions, pathogen genetics, and contemporary surveillance techniques, promises to open up new opportunities to advance understanding of complex multihost systems. many pathogens persist in multihost systems, making the identification of infection reservoirs crucial for devising effective interventions. here, we present a conceptual framework for classifying patterns of incidence and prevalence, and review recent scientific advances that allow us to study and manage reservoirs simultaneously. we argue that interventions can have a crucial role in enriching our mechanistic understanding of how reservoirs function and should be embedded as quasiexperimental studies in adaptive management frameworks. single approaches to the study of reservoirs are unlikely to generate conclusive insights whereas the formal integration of data and methodologies, involving interventions, pathogen genetics, and contemporary surveillance techniques, promises to open up new opportunities to advance understanding of complex multihost systems. advancing our understanding of reservoirs most disease-causing organisms, including many important human, livestock, and wildlife pathogens, are capable of infecting multiple hosts [ ] [ ] [ ] . therefore, determining how hosts enable persistence [ ] and which hosts are crucial for the persistence of these multihost pathogens [ ] is essential for the design of effective control measures. failure to establish this understanding can hamper policy formulation and lead to ineffective or counter-productive control measures with costly implications for socially, economically, or ecologically important populations. reservoirs of infection can be ecologically complicated structures comprising one or more interacting populations or species (box [ ] ). although a range of developments has led to better theoretical conceptualisation of reservoirs [ ] [ ] [ ] [ ] [ ] , their empirical characterisation remains a challenge. in this article, we review methods currently used to characterise each of the components that comprise a reservoir according to the framework in box . specifically, we first present a conceptual approach for classifying patterns of incidence and prevalence (see glossary) that result from the connectivity between source and target populations (black arrows in figure i in box ). we then review methods that allow us to identify maintenance or nonmaintenance populations (squares or circles in figure i , box ), how they are connected (arrows in figure i , box ), and the role that each of these populations has in maintaining the pathogen (i.e., reservoir capacity). long-term ecological data on multihost systems are sparse and challenging to collect [ ] [ ] [ ] ; this, combined with the inherent difficulty of identifying reservoirs of infection, means that each data set or approach in isolation is unlikely to result in a sufficient evidence base to inform control strategies. here, we further discuss how to enrich this evidence base. almost inevitably, the need to intervene will precede adequate understanding of the dynamics of reservoir-target systems. our central thesis is that interventions that are meticulously planned to optimise both the immediate short-term benefits to the target population and the longer-term understanding of how reservoirs function, applied together with a formal integration of data and methods [ ] , can provide powerful new opportunities for studying complex multihost systems (e.g., [ ] ). patterns of incidence and prevalence in the target data on patterns of incidence and prevalence provide indirect information on the connectivity between source and target populations (i.e., black arrows in figure i , box ). building upon the 'community-epidemiology continuum' framework developed by fenton and pedersen [ ] , specific patterns can be assigned to 'zones' (figure and table ) defined in relation to the relative magnitudes of the force of infection from one or more source(s) (x-axis in figure ; thickness of arrows in figure i , box ), and r ,t , the basic reproduction number of the pathogen within the target. if the target population is a 'dead-end' host from which transmission does not occur, then r ,t = . for a sufficiently low force of infection, the interval between cases in the target host is longer than the infectious period of single cases (figure , zone a) and cases are not directly linked. as the force of infection from alternative sources increases, we observe cases in the target population with increasing frequency. at higher values, cases can overlap in time and space but remain epidemiologically unlinked and, as long as variability in the pathogen is high enough, genetically distinct ( figure , zone b) . our study of epidemiology is usually motivated by the need to control disease in a particular host population or a subset of a population. following haydon et al. [ ] , we refer to this as the 'target population'. populations that are direct sources of infection for the target are termed 'source populations'. a 'reservoir of infection' is defined with respect to a target population as 'one or more epidemiologically connected populations or environments in which a pathogen can be permanently maintained and from which infection is transmitted to the target population' [ ] . some reservoirs can be simple and comprise a single nontarget host population ( figure ia) . however, they can comprise a more structured set of connected host subpopulations termed 'maintenance community' (figure ib-d) . individually, some of these populations can maintain the pathogen ('maintenance populations'), whereas others cannot ('nonmaintenance populations'). thus, infection reservoirs can be constituted in a variety of ways. reservoirs can be wildlife species [e.g., possums (eichosurus vulpecula) as a reservoir of bovine tb in cattle in new zealand; or wildebeest (connochaetes taurinus) as a reservoir of malignant catarrh fever for cattle in tanzania]; domesticated species (e.g., dogs as a reservoir of rabies for humans in many developing countries; cattle as a reservoir of escherichia coli for humans in the uk), or subsets of the same species (e.g., adults as a reservoir of respiratory syncytial virus for children, men as an element of the reservoir of human papillomavirus for women). other definitions of reservoirs have been proposed [ , ] . although ashford's [ ] definition is appealing for its generality, and drexler et al.'s [ ] for its evolutionary perspective, we use haydon et al.'s [ ] due to not only its acceptance within the epidemiological literature, but also its direct application for designing interventions. arrow thickness denotes rate of transmission. in (a), the reservoir comprises a single source maintenance population that transmits to a nonmaintenance target population. in (b), the reservoir comprises two connected nonmaintenance populations (of which one is the source) that together form a maintenance community. in (c), the target is a maintenance population and a source of infection and, thus, is part of the reservoir. in (d), the reservoir comprises three nonmaintenance populations, together forming two minimal maintenance communities each capable of maintaining the pathogen; together, these form a larger maintenance community. in (e), the reservoir comprises a maintenance community of multiple connected nonmaintenance populations, four of which are source populations. modified from [ ] . trends in ecology & evolution may , vol. , no. target populations in which limited transmission can occur but r ,t < will, when the force of infection from the source is low, exhibit the classic 'stuttering chain' dynamics ( figure , zone c) in which outbreak sizes follow an overdispersed distribution [ ] . as r ,t ! , these outbreaks can become large. however, as the interval between introductions becomes shorter than the average duration of outbreaks, we observe a pseudo-endemic pattern in which the target population can appear to be a maintenance population even when it is not ( figure , zone d). systems in which r ,t is close to present particular threats because small changes in their epidemiology within the target population, through either pathogen evolution or changes in the target population structure, can cause r ,t to exceed and lead to an endemic situation and/or epidemic behaviour [ ] . if r ,t > then any spill-over events can give rise to substantial epidemics. stochastic extinction will still occur frequently if r ,t is only slightly greater than (figure , zone e); however, if the outbreak 'takes off' or r ,t >> , then there are three broad possible outcomes: (i) the target population sustains a major epidemic after which the pathogen becomes extinct in the target population [e.g., distemper virus in wolves (canis lupus) and harbour seals (phoca vitulina)]; (ii) the target population sustains a major epidemic after which the pathogen proceeds towards an endemic state in the target population (e.g., hiv; the target population is then a square in figure i , box ); (iii) control measures within the target population reduce r ,t to below , so a major epidemic is averted and the pathogen becomes extinct in the target population (e.g., severe acute respiratory syndrome). if r ,t > and the force of infection from the reservoir is large (figure , zone f), fadeout is unlikely (e.g., southern african territories strains of footand-mouth disease in cattle in sub-saharan africa). dynamics ranging from pseudo-endemicity to true endemicity lie on an ascending diagonal from right to left ( figure , arrow), along which increasing r ,t compensates for a declining force of infection from the reservoir. these different situations are likely to be hard to distinguish using patterns of incidence and prevalence alone. however, higher resolution spatiotemporal data and pathogen genetic sequence data, together with sophisticated analytical techniques such as state-space modelling, can provide some of the necessary tools to examine these patterns (see 'connectivity within the reservoir'). given the challenges of isolating pathogens from wildlife populations, patterns of incidence and prevalence are typically obtained from longitudinal seroprevalence surveys or age-seroprevalence curves. these have been used to investigate infection dynamics of various multihost systems, such as canine distemper virus (cdv) in carnivore communities of the serengeti [ , ] , kenya [ ] , and yellowstone [ ] , trypanosoma cruzi in wildlife hosts in the usa [ ] and hepatitis e in wild boars (sus scrofa) in europe [ ] . however, their interpretation remains fraught with uncertainties mainly owing to cross-reactivity, declining antibody titres, cut-off thresholds used to distinguish positive and negative reactions, and difficulties with the detectability of antibodies because these depend on the relation between immunity and infection resistance (e.g., a detectable antibody does not always imply protection and the time of exposure remains unknown for pathogens that create life-long immunity in the host) [ ] . new statistical approaches, such as latent class methods and site-occupancy modelling, have been suggested recently to improve estimates of prevalence from imperfect tests by allowing uncertainty in the detection of infection state [ ] . although still in early stages of development, advanced modelling techniques, such as bayesian process models, can enable inferences of timing of exposure from ageseroprevalence data, accounting for non-stationary epidemiological dynamics [ ] , and/or detect cross-species transmission [ ] , to identify which host species is the most likely source of infection. methods to identify plausible reservoirs typically focus on thresholds that define individual populations as maintenance or nonmaintenance (squares or circles in figure i , box ). therefore, we discuss critical community size (ccs) as an intuitive measure of persistence that can be traced back to the reservoir framework proposed by haydon et al. [ ] . ccs can be loosely defined as the host population size below which a pathogen cannot persist [ , ] . thus, a maintenance population can be defined as a host population in which a pathogen persists because the population size is greater than ccs, whereas a nonmaintenance population is one smaller than ccs [ ] . however, there are several challenges to the study of ccs in practice. x-axis) and target-to-target transmission represented here by the basic reproduction number in the target population (r , t ; y-axis). we note that the source of infection can be a reservoir, a maintenance population, or a nonmaintenance population. further details of the dynamic and genetic signatures of each zone are provided in table (main text). trends in ecology & evolution may , vol. , no. the first challenge is to define the population in which persistence is to be measured. given that persistence is sensitive to the complex relation between demographic and epidemiological factors, it is difficult to estimate in the presence of population structure [ , ] ; therefore, ccs is most commonly discussed in the context of single well-mixed populations, although these are rare in natural systems. the second challenge is in defining persistence, particularly because any estimate of ccs is likely to be sensitive to the choice of persistence metric [ ] . in his original work, bartlett defined ccs as the size of a population in which extinction was as likely as not following a major outbreak [ ] . however, persistence might also be measured from an initial condition corresponding to the endemic equilibrium [ , ] . lloyd-smith et al. [ ] point out that the relation between persistence and population size is not well described as a step function, but instead increases in a gradual manner. ccs can also be thought of in relation to the probability of extinction within a given time or the time until a given proportion (usually %) of introductions (or simulations) have gone extinct [ ] . once appropriate definitions are adopted, the final challenge is estimating ccs. the main approaches used are: (i) empirical observation, which consist of plotting incidence data against population size [ , [ ] [ ] [ ] ; (ii) analytic expressions [ , [ ] [ ] [ ] , although all approximations so far exclude many processes relevant to ccs, such as latency, spatial heterogeneity, seasonality, age structure, and nonexponential infectious periods [ , ] ; and (iii) stochastic computer simulations, in which parameterised compartmental models are used to generate distributions of persistence times for populations of different sizes and from which ccs can be estimated [ , ] . however, these studies assume a linear relationship between population size and recruitment, which is unrealistic in natural systems [ ] . beyond studies of measles [ ] [ ] [ ] , little work has been done to estimate ccs. next-generation matrix (ngm) methods have also been used to identify reservoir communities from endemic prevalence data. this method estimates a threshold that is similar to r (or the effective reproduction number in the endemic case) separately for individual host populations within a multigroup population rather than averaging across all populations [ ] . for example, using ngm, mallards and other dabbling ducks were reported to be part of the most likely reservoir community of influenza a in the global water bird population [ ] . however, this method focuses strictly on whether persistence is possible (i.e., whether the appropriate reproductive number exceeds ), and ignores the stochasticity and nonequilibrium dynamics that are central to classical thinking on ccs. also, implementations of the method have relied on the strong assumption that infection prevalence is at endemic equilibrium in all host species. connectivity within the reservoir: tracing transmission identifying which populations constitute the reservoir requires understanding how the populations are epidemiologically connected to each other. here, we discuss two approaches used to trace transmission within the reservoir and between the reservoir and a target population: simulations and modelling, and genetics. evidence to test the hypothesis that a particular population is a source of infection can also be acquired through real-world interventions that either reduce prevalence of disease in the putative source or block source-totarget transmission while monitoring incidence in the target. these are discussed in a subsequent section. statistical modelling is increasingly used to identify plausible sources of infection. one of the advantages of modelling is that they can be used for partially observed processes [e.g., approximate bayesian computation [ , ] , state-space models (ssm; [ ] ), and markov models [ ] [ ] [ ] ]. for example, ssms make an explicit distinction between data that can be observed (e.g., infected individuals detected by surveillance) and the underlying process itself, which might be largely unobserved (e.g., all infection events). beyer et al. [ ] constructed an ssm of rabies persistence in the serengeti district in tanzania that used records of humans reporting to hospital with dog bite injuries. using a statespace implementation of a metapopulation process describing the unobserved process of dog-to-dog transmission between villages, they were able to estimate parameters capturing the effects of intervillage distance and the size of dog populations on rabies dynamics. based on these, they inferred that it was more likely that dog rabies infections were being imported from unvaccinated domestic dogs in outlying districts, or from wild peri-urban carnivores in the serengeti district itself, rather than from wildlife residing within the national park. despite their advantages, inferences rely on valid assumptions being made about the biological processes embodied in model structure. given a possible set of transmission parameters, plausible reservoirs of infection can also be identified using simulation models [ , , ] . transmission parameters are typically obtained from epidemiological, demographic, or genetic data, and can be manipulated to explore the sensitivity of the reservoir dynamics to these parameters. for example, cross et al. [ ] used an age-structured model of two interacting elk populations (free-ranging and those receiving supplemental feeding) to investigate the extent to which dispersal from feeding grounds could explain changes in brucellosis seroprevalence in elk around the yellowstone ecosystem. they found that r in the freeranging elk population (the target population) had increased to above over the past years, probably due to changes in elk aggregations that led to enhanced elk-toelk transmission (i.e., moved from zone c to e in figure ). tracing transmission using genetics genetic inference of cross-species transmission has so far tended to borrow analytical approaches from population genetics and phylogeography [ ] [ ] [ ] (box ). genealogybased methods have particular appeal because, for many pathogens, the accumulation of mutations takes place on approximately the same timescale as transmission. if transmission chains are genetically distinguishable, they can provide complementary information to incidence and prevalence data. for example, given sufficient pathogen genetic variability in the reservoir, genetic data should readily distinguish rare spillover and subsequent transmission in the target from scenarios involving the same incidence due only to a high box . using pathogen genetics to untangle reservoirtarget dynamics methods based on discrete ancestral state inference offer an appealing statistical way to approach the problem of multihost transmission by fitting probabilistic models to pathogen sequence data [ ] . in these methods, genealogies are constructed from the data, and host associations (states) observed at the tips of the trees are used to estimate the conditional probability of being affiliated with a particular host population along all interior branches. transmission events between host populations and, thus, the net contribution of the reservoir to dynamics in the target, can be enumerated through markov jump counts [ , ] . a more formal population genetic framework, centred on joint estimation of population sizes and migration rates across all patches [ , ] , can similarly be adapted to deal with pathogen gene flow [ ] . although novel approaches based on genetic data open up intriguing opportunities, their resolution has defined limits. as introductions into the target become more frequent, it is increasingly difficult to distinguish contributions of the reservoir from continuous transmission within the target. increasing genetic resolution by using longer sequences can compensate for this, but only to the point of sequencing entire pathogen genomes. the ability of genetic markers to resolve cross-species transmission processes will also be reduced by potential pathogen flow from the target population back into the reservoir [ ] . genetic inference of reservoir-target dynamics has so far also received little formal testing. there is strong reason to suspect that biased sampling can have a profound influence on the inferences generated. for example, genetically unsampled sources of infection will not only remain undetectable, but their contribution will also be wrongly attributed to populations included in the sample (a problem akin to that caused by 'ghost populations' in population genetics [ ] ). moreover, inferred transmission dynamics can depend on the relative spatial and temporal density of sampling among host populations. finally, stuttering chains within the target population can boost the frequency of cases (compare zones a and c in figure , main text) and, hence, the likelihood of detection under sparse sampling; if unaccounted for, this can lead to overestimation of cross-species transmission rates. these complexities can generate significant challenges for the investigation of reservoir-target systems because balanced, representative sampling, proportional to the incidence in each host, is rarely achievable. therefore, developing robust ways to deal with problems related to sampling in the context of genealogical inference and the reconstruction of transmission histories remains an important focal area for future research. trends in ecology & evolution may , vol. , no. force of infection from outside the target population (figure , zones b and c, and zones d and e) [ , ] . a reservoir can comprise multiple connected populations of the same or different species (see figure e in box ), and, thus, can be represented as a metapopulation. to assess whether this metapopulation is capable of supporting pathogen persistence, we can draw a parallel with ecological theory. representing the reservoir as a metapopulation, we can extend the notion of metapopulation capacity [ ] to that of reservoir capacity (box ). reservoir capaci-ty, l' m , is a measure of the potential of a structured host population to support pathogen persistence in the absence of external imports and, thus, can be used to assess whether a population constitutes a reservoir. a useful benefit is that associated patch values v i (i.e., the relative contribution of each population to overall persistence; box ) can be used to prioritise populations when designing interventions. the modelling framework encapsulates three processes (within-population processes, transmission between populations, and community-level persistence) and is normally used to investigate one of these processes when it is possible to parameterise the other two. the notion of 'metapopulation capacity' [ ] captures in a single number l m the capacity of a fragmented landscape, comprising patches, to support the long-term persistence of a species in the absence of external imports. by analogy, we define 'reservoir capacity' as the capacity of a metapopulation to support the longterm persistence of a pathogen. it can be regarded as a measure of effective host abundance, weighted to take into account structural factors, such as local population sizes and connectivity, that influence fadeout rates within populations and transmission between them. the dynamics of a general metapopulation are governed by equation i (figure i) , in which invasion and fadeout rates are functions of infection status of other populations, as well as factors such as population sizes and transmission rates. persistence in the metapopulation is controlled by the ratio of population invasion events to disease fadeouts, and these are balanced at equilibrium. reservoir capacity for this general model is defined in equation ii ( figure i ). reservoir capacity also suggests a persistence threshold. in this deterministic model, a pathogen persists in a given landscape if and only if l m > , corresponding to the threshold above which equation i has a stable nontrivial equilibrium. although parameterising this kind of metapopulation model is challenging, methodology shared between ecologists and epidemiologists [ ] can allow assessments of likely persistence. an attractive feature of this approach is the ability to estimate patch values, v i , which are measures of the contribution of individual populations to the persistence threshold that is used to guide interventions. for example, figure ii shows the relative contribution of villages in the serengeti district, tanzania, to local rabies reservoir capacity, estimated from the beyer et al. [ , ] model discussed in the main text. although the village shaded in red is the biggest both in terms of size and patch value, for villages with approximately dogs, the patch values range from . to . depending on their spatial location relative to other villages ( figure iib ). [i] [ii] rate of change in p i , the probability that infecƟon is present in populaƟon i enriching the evidence base no one line of evidence is likely to support unambiguous inferences about the structure and functioning of a reservoir system. however, two general strategies are worth emphasising: interventions embedded into adaptive management and data integration. interventions embedded into adaptive management programs interventions are normally designed to maximise the benefits of disease control [ ] . however, they must often be devised with an incomplete understanding of the overall disease dynamics. we argue that using interventions as quasi-experiments can provide valuable opportunities to learn more about the functioning of a reservoir (see examples in table ). through adaptive management [ , ] , disease control objectives can be met while generating and enriching the evidence base to improve future control policies and resource allocation. interventions that generate substantial (and, thus, more easily measurable) changes to the system are the most likely to provide useful information. such interventions can be akin to 'press' (sustained action; e.g., long-term vaccination) or 'pulse' (one-off action; e.g., single culling or vaccination campaign) phenomena that are familiar to ecologists [ ] , or 'block' perturbations (where potential transmission between reservoir and target is impeded; e.g., fences). power can be assessed from predictions based on classical sensitivity or elasticity analysis [ ] . interventions that induce no changes can also be informative if, for example, they allow us to rule out a particular transmission route or source population. what can be learned from such interventions is dependent on whether they enable relevant hypotheses to be tested. it is also important to note that these interventions can alter the target-reservoir transmission dynamics, leading to difficulties in distinguishing causes and effects of the intervention. for example, the randomised badger culling trial conducted over km and a -year time period [ ] generated a wealth of data and analysis that should be instrumental in determining the circumstances in which badger culling might usefully contribute to the effective control of bovine tb in the uk. however, it might not be simple to determine whether particular changes in the reservoir-target disease transmission dynamics were a direct or indirect (due to dispersal and behaviour change) consequence of the culling. the main challenge in using adaptive management lies in balancing knowledge gain that enables improved future control with achieving the best short-term outcome based on current knowledge [ ] . it might be that an intervention that optimises the short-term outcome (e.g., one resulting in the greatest reduction of disease prevalence in the target) is also the one that provides the greatest statistical power to test the hypothesis of interest. in other situations, there can be a trade-off between the short-term goals of rapid disease control and the longer-term goals of learning about the system to optimise future control. this is particularly true given the cost of allocating resources to monitoring, the need to include experimental control areas [ ] , and the challenge of defining efficient experimental designs (e.g., stepped wedged trial; [ ] ) for the hypothesis being tested [ , ] . for example, faced with limited knowledge about the dynamics of chronic wasting disease (cwd) in wisconsin (us), the us department of natural resources established an adaptive management programme to eradicate cwd from the area [ ] . the intervention was based on random deer culling, but a key component of the program was the collection of lymph nodes and brain tissue from the culled and harvested deer to assess the spatial distribution of cwd and provide further insights into its epidemiology. in most cases, understanding reservoirs dynamics requires the use of multiple data sources. integration of findings can occur at the analysis or study design stage [ ] or later, using techniques such as meta-analysis or mathematical modelling (e.g., [ ] ). triangulation of multiple sources should improve understanding of the validity and generalisation of inferences [ ] . by synthesising several lines of evidence, lembo et al. [ ] found support for the hypothesis that domestic dogs, rather than wildlife, constitute the maintenance population for canine rabies in northern tanzania. their analyses included post-hoc integration of long-term case monitoring data (suggesting that rabies can persist in high-density domestic dog populations), genetic data (showing that a single rabies virus variant circulates among a range of species), and analysis of incidence patterns (indicating that spillover from domestic dog populations initiated only short-lived chains of transmission in other carnivores, consistent with zone c in figure ). ultimately, we seek a formal statistical integration of different sources of evidence that can be used to characterise reservoir systems. such integrative approaches are rare, but increasingly powerful methods are being developed. for example, genetic, spatial, and epidemiological data can now be combined to enable detailed reconstruction of transmission within and between host populations (e.g., [ , ] ) and time-calibrated phylogenies can be layered with geographical and epidemiological data in a joint framework that enables estimation of the frequency and directionality of interspecies transmission (e.g., [ , ] ). for example, based on viral gene sequences and epidemiological data, faria et al. [ ] reconstructed the cross-species transmission history of rabies virus between north american bats and identified ecological and evolutionary constraints on transmission patterns. latent variable models that explicitly parameterise both process and observation models are also well suited to combining data types, particularly when observations are sparse [ ] . developing statistically rigorous analytical methods that integrate multiple data layers is a challenging but exciting area, and key to future progress in infectious disease ecology [ , ] . box summarises outstanding questions in the study of reservoirs of infection. each of the approaches discussed here provides important threads of evidence on its own. however, these threads are part of a more extensive tapestry and, when viewed in isolation, they convey only a fragmentary understanding of how reservoirs work. appropriately designed interventions can simultaneously provide direct tests of disease control methodology, deliver health benefits within the target population, and create important research opportunities that can advance understanding of reservoir dynamics. however, to realise these benefits fully, we must form broad-based interdisciplinary teams, engage with their full range of expertise from the earliest planning stages, and support them throughout the lifetime of the intervention. understanding reservoir structure and function requires not only an integration of approaches to data collection and analysis, but also a step-change in the way that research communities integrate their activities with animal and human health practitioners. although there are increasingly powerful tools to characterise different components of reservoir-target systems, there are two central challenges that remain to be overcome: (i) determining persistence thresholds for different host populations; and (ii) estimating the rates of cross-species transmission. instead, we typically make qualitative inferences (as shown in table , main text), which inevitably results in less effective control policies. advances in the use of genetic data and widely available serology data sets, including their integration with relevant ecological theory such as reservoir capacity, offer promising new ways to approach these challenges. the use of interventions as quasi-experiments can provide robust empirical 'top-down' approaches to characterising reservoirs, particularly if they are designed as 'crucial experiments' [ ] that test among multiple hypotheses to eliminate host populations progressively as contributing to a reservoir. however, this approach raises two other challenges: (iii) how to design interventions that allow us to test the quantitative predictions of the level of control needed to eliminate infection in one population; and (iv) how to coordinate the close engagement of the research community with managers charged with improving veterinary and public health. trends in ecology & evolution may , vol. , 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genetic diversity could buffer populations against epidemics in nature, but it is not clear how much diversity is required to prevent disease spread. recent theoretical and empirical studies, particularly in daphnia populations, have helped to establish that genetic diversity can reduce parasite transmission. here, we review the present theoretical work and empirical evidence, and we suggest a new focus on finding ‘diversity thresholds.' it seems to be conventional wisdom that genetically homogeneous populations suffer from more severe pathogen outbreaks than diverse populations (elton, ; sherman et al., ; schmid-hempel, ; altizer et al., ) . infection is more likely to be transmitted between genetically similar hosts (anderson and may, ) , and upon encountering resistant hosts, parasites would likely die, fail to successfully reproduce (anderson and may, ) , or otherwise be removed from the population (keesing et al., ) . as such, the risk of infection, especially by virulent pathogens, may select for outcrossing over uniparental forms reproduction, such as self-fertilization or parthenogenesis king et al., ; morran et al., ) , resulting in an overall increase in genetic diversity (king et al., ) . there may not seem to be an escape from disease, but genetic diversity in host populations may reduce the risk of infection. the empirical link between disease spread and genetic diversity has its origin in agricultural research. agricultural fields represent environments in which plants are selected for high yield, and may therefore exhibit less genetic polymorphism than those in the wild. it is well known that disease epidemics have devastated agricultural monocultures (for example, rice blast, zhu et al., ) , and that monocultures are typically more susceptible to outbreaks than diverse mixtures of crops (mundt, ) . this association between low diversity and high disease incidence is called the 'monoculture effect' (for example, elton, ; leonard, ; garrett and mundt, ; zhu et al., ; pilet et al., ) . here, we examine how genetic diversity affects the spread of disease in natural populations. we also consider the theoretical basis for the monoculture effect in host populations, and suggest that there may be a 'diversity threshold' for disease spread. the most notable examples of the monoculture effect in natural populations come from the dramatic epidemics in small populations of endangered species, particularly mammals (for example, o'brien et al., ; thorne and williams, ) . genetic bottlenecks have reduced the genetic variability in cheetahs, particularly at the major histocompatibility complex, and endangered populations of these animals have been decimated by coronavirus epizootics (o'brien et al., ) . similarly, the endangered black-footed ferret may have been extirpated from its natural habitat, because low genetic diversity aided the spread of a virulent canine distemper epizootic (thorne and williams, ) . range expansion and habitat isolation caused by human activities can also generate small, founder populations with low genetic diversity. newly-colonised, western populations of italian agile frogs (rana latastei) are genetically depauperate, and they have an increased susceptibility to a novel, emerging ranavirus (pearman and garner, ) . similarly, dam construction in the senegal river basin likely permitted the rapid expansion of snails (biomphalaria pfeifferi ), which serve as the first-intermediate host for the human disease schistosomiasis (campbell et al., ) . recently established biomphalaria snail populations are genetically homogenous compared with those in natural habitats in zimbabwe; they are also more susceptible to infection and this increases the opportunity for parasite transmission to humans (campbell et al., ) . by reducing individual-level and population-level genetic heterozygosity, inbreeding can increase host susceptibility to infectious parasites (dwyer et al., ; acevedo-whitehouse et al., ; spielman et al., ; ellison et al., ) . in wild populations, acevedo-whitehouse et al. ( ) found that heavily inbred california sea lions were more infected, and consequently, may act as pathogen reservoirs, spreading parasites in sea lion populations. but, is increased susceptibility directly due to reduced diversity, or does inbreeding depression have an effect by compromising host condition? by manipulating the levels of inbreeding in drosophila melanogaster, in laboratory experiments spielman et al. ( ) confirmed that the increase in disease susceptibility resulted from a lower frequency of resistance alleles in the population, and not by generalized inbreeding effects. inbreeding effects were similarly excluded as a reason for why offspring from inbred populations of daphnia, a freshwater crustacean, were more susceptible to a vertically-transmitted parasite than those from outbred populations (ebert et al., ) . finally, kerstes and wagner ( ) found that inbreeding increased parasite-induced mortality in the red flour beetle (tribolium castaneum) by prolonging development time, but it did not increase susceptibility to infection. founder populations provide the opportunity to examine the effects of inbreeding and small population size on the link between genetic diversity and parasite resistance. for example, in a comparison of founder versus ancestral mainland populations of deer mice, meagher ( ) found that inbred, island populations in lake michigan had higher infection levels and lower genetic diversity. the link between diversity and parasite spread has even been revealed when comparing large and small founder populations. hawks colonizing smaller galápagos islands possessed lower genetic diversity, produced low antibody titer, and had a higher abundance of parasites than more outbred populations on larger islands (whiteman et al., ) . uniparental forms of reproduction, such as self-fertilization or parthenogenesis, should have similar consequences for parasite resistance as biparental inbreeding. along these lines, self-fertilizing populations and inbred sexual populations were both found to have higher infection rates by a trematode parasite compared with outbred sexual populations of topminnows (poeciliopsis monacha) (lively et al., ) . in another species of partially-selfing fish (kryptolebias marmoratus), ellison et al. ( ) found that outcrossing increased the genetic diversity of wild populations and decreased their susceptibility to multiple parasites. mating systems can also directly affect genetic diversity and parasite resistance (busch et al., ; williams et al., ) . for example, in eusocial insect colonies, queens can mate with a single male or with multiple males (polyandry), which determines the level of relatedness among individuals within a colony. high relatedness among individuals in a population can enhance the evolution of cooperation (hamilton, a (hamilton, , b, , but the genetic similarity between individuals may also facilitate the spread of parasites (shykoff and schmid-hempel, ; schmid-hempel, ) . as such, multiple mating has been suggested as an evolutionary response to parasite pressure (hamilton, ; sherman et al., ) , which may counteract the high risk of parasite transmission and increase the overall productivity of the colony (schmid-hempel, ; schmid-hempel and crozier, ; brown and schmid-hempel, ) . numerous studies on ants and bees have indeed found that multiply mated queens form more resistant colonies schmid-hempel, , ; tarpy, ; hughes and boomsma, ; tarpy and seeley, ; seeley and tarpy, ) , and that offspring fathered by different males do vary in susceptibility to infection (baer and schmid-hempel, ) . ultimately, the balance between the costs (for example, within-colony conflict, reduced offspring output) and benefits (for example, resistance to a range of parasites) associated with heterogeneity in colonies may determine the optimal level of polyandry (baer and schmid-hempel, ; van baalen and beekman, ) . polygyny (the presence of multiple queens within a single colony) can also decrease the relatedness among individuals and increase the variety of resistance alleles in the colony. studies in which the number of founding queens was experimentally manipulated have confirmed that colonies founded by multiple queens have lower parasite loads (liersch and schmid-hempel, ; reber et al., ) . in addition, workers from polygynous colonies of an ant (cardiocondyla obscurior) were better at detecting disease and removing infected individuals from the nest than workers from nests having a single queen (ugelvig et al., ) . increases in infection prevalence in the wild is associated with genetic bottlenecking and inbreeding, induced by founder effects or mating systems. thus, host population genetic diversity seems to have an important role in buffering populations against epidemics. but, how exactly does genetic diversity reduce disease spread? how much diversity is necessary? an association between genetic diversity and disease spread might be detected by categorizing populations as being either genetically homogenous or diverse. this comparative method can tell us that diversity matters, but does not indicate the amount of genetic diversity required for a population to be resistant, or the 'diversity threshold' . recently, two insightful empirical studies have quantified the effect of genetic diversity on resistance in host populations. altermatt and ebert ( ) and ganz and ebert ( ) conducted semi-natural mesocosm and lab experiments, respectively, whereby monoclonal and polyclonal daphnia populations were exposed to microparasites. parasites spread significantly faster (altermatt and ebert, ) and infection rates are higher (ganz and ebert, ) in host monocultures compared with 'polycultures' of several genotypes with higher allelic diversity. these studies suggest that the relationship between host diversity and infection may not be complex, and that a 'handful' of host genotypes in the population can be enough to hamper parasite transmission. the benefits of host genetic diversity, however, may also depend on the genetic diversity of the parasite population (boomsma and ratnieks, ; van baalen and beekman, ; ganz and ebert, ) . if the parasite population is genetically homogenous, increases in host population genetic diversity might boost the opportunity for parasites to encounter a susceptible host (boomsma and ratnieks, ; van baalen and beekman, ) . alternatively, in a diverse parasite population, there is a high probability that one of a diverse set of parasite genotypes can infect a homogeneous host population (van baalen and beekman, ) and genetically diverse host populations are at an advantage. consistent with these ideas, ganz and ebert ( ) found no difference in infection levels among experimental daphnia monocultures and polycultures when populations were exposed to a single-parasite genotype; however, polycultures were more resistant when populations were exposed to multiple parasite genotypes. there has been surprisingly little theoretical work on the effect of genetic diversity on disease spread. two models suggest that genetic variation in host susceptibility would not affect infectious disease spread (springbett et al., ; yates et al., ) , but it might reduce the severity of infection (springbett et al., ) . in these models, hosts varied in susceptibility to a single pathogen strain, but no host genotype was completely resistant to infection. in contrast, lively ( a) found that host genetic diversity could reduce the risk of disease spread, assuming that each host genotype was susceptible to a different parasite genotype. this assumption is consistent with the 'matching-alleles' model for infection (frank, ; otto and michalakis, ) . the matching-alleles model is a useful framework for studying self/non-selfrecognition systems in animals, and it is supported by studies on invertebrate immunity (grosberg and hart, ; carius et al., ; dybdahl et al., ; duneau et al., ; luijckx et al., ) . in addition, the framework seems robust to the assumption of singlegenotype specificity (agrawal and lively, ; engelstaedter and bonhoeffer, ) . the more recent model suggests that increases in the genetic diversity of host populations could have a large effect on disease spread and prevalence at equilibrium (lively, a) . the model assumes that there are no co-infections, and that each parasite genotype can only infect one genetically determined resistance phenotype in the host population, which is the standard assumption of the matching-alleles model for infection. the results suggest that r for each parasite genotype i depends on total host density, as well as the frequency of the matching host genotype, where matches between host and parasite genotypes yield an infection. thus, disease transmission is both density and frequency dependent. the effect of host density on r is asymptotic on bg i , where g i is the frequency of the matching host genotype, and b is the number of parasite propagules produced by each infection that make contact with a host (lively, a) . thus, b is equal to the total number of propagules produced by an infection multiplied by the frequency of propagules that contact a host. for large host populations (n ) the effect of further increasing the host population size has little effect; but, increasing the number of host genotypes has a large effect, because increasing the number of host genotypes decreases the frequency (g i ) of each genotype. under parasite-mediated, frequency-dependent selection, the frequency of each host genotype would be expected on average to be approximately /g, where g is the total number of host genotypes in the population. under these conditions, r for large populations is approximately b/g. this result suggests that experimentally doubling the number of host genotypes in the population would reduce r by one half, and that this would be roughly true even if the experiment increased the total number of hosts in the population (assuming the population is already large). the analytical results also suggest that the parasite would die out, following the addition of genetic diversity to the host population, provided that the frequency of each host genotype declines to less than /b. we used computer simulations to examine the gist of these ideas. the simulations assumed a haploid host with two loci coding for resistance. each locus could have up to three alleles for a total of nine different genotypes. each of the host genotypes could be infected by one of nine different parasite genotypes, consistent with the matching-alleles model for infection. in these simulations, birth rates of the host were density dependent, and infection reduced the intrinsic birth rate by % (the parameters where chosen for illustrative purposes). the details of the simulation are given in lively ( b) . we began the simulation with two alleles at one locus and three alleles at the other locus, giving six possible host genotypes. an uninfected host population was initiated at carrying capacity (k ¼ ), where the number of hosts of each genotype was determined by randomly assigning allele frequencies at the two loci. at generation , one host of each genotype was introduced as infected. thereafter, the infected hosts of each genotype were introduced into the population with a probability of . per generation, to simulate immigration of infected individuals. we started by assuming b ¼ , meaning each infection produced nine propagules that contacted a host. from the analytical results we would expect under that the average value for r would be b/g ¼ / ¼ . (where g is the number of genotypes). as such, the pathogen would be expected to spread in the population, as was indeed the case (figure a) . after an initial oscillatory period, the gene frequency dynamics stabilized (figure a) , and the prevalence of infection also stabilized for the parameter values considered here (figure b) . r converged on the predicted value of . (figure c) . we then introduced a third allele at the second locus at generation , which increased the number of possible genotypes from six to nine. the allele quickly spread, as it conferred resistance on three of the nine possible genotypes for which there was no matching parasite genotype (figure a ). average r quickly dropped to below as the allele spread in the population (figure c) , and the frequency of infection declined sharply (figure b) . matching parasite genotypes were introduced into the population by migration (at a rate of . per genotype per generation), which lead to selection against the new allele after it became common, as well as to a slight increase in r (figure c ). this resulted in sufficient selection to equalize allele frequencies so that the frequency of each genotype approximated /g. at this point, r was equal to one (b/g ¼ / ¼ ), and parasite prevalence fell close to zero, but was maintained at a low level by immigration (figure b) . the point is that introducing a single novel allele in the host population increased the number of possible genotypes by %. this lead to virtual elimination of the parasite, as the prevalence of infection plummeted from about % to near zero. a reduction in prevalence occurred despite the fact that matching parasite genotypes were also introduced into the population, and that the host population size remained large (that is, close to individuals; results not shown). clearly, under the assumptions of the present model, small increases in allelic diversity can cause dramatic reductions in parasitism, even in very large host populations. in addition, elimination of the pathogen is not necessarily followed by a loss of genetic diversity in the host population, as the different host genotypes are selectively neutral in the absence of parasite pressure (figure a) . the available data and the model are consistent with the idea that genetic diversity in host populations can reduce the spread of disease. however, a practical question arises: would the beneficial effect of adding hosts with novel genotypes, in order to increase local genetic diversity, outweigh the positive effect of increasing population size on r ? a possible answer is also suggested by the model, which suggests that the effect of increasing population size on r shows diminishing returns with host density, such that r is asymptotic on b/g ( figure ). as such, while increasing host population size does strongly affect r in small host populations, it has a small effect in large host populations (figure ). this suggests that increasing genetic diversity can still reduce parasite prevalence, even though host population size is also increased. the results in figure suggest that boosting genetic diversity could overcome the effect of increasing host population size, even when the latter is increased by fourfold. critically, the diversity threshold does not work by simply reducing the population size of the individual genotypes. the threshold, in fact, was calculated by assuming an infinite host population size. rather it works by reducing the probability of successful infection by reducing the frequency of matching host genotypes for each parasite genotype. consistent with results from agricultural populations, the existing literature suggests that high genetic diversity could buffer host populations against disease spread. although observational studies from natural populations of vertebrates (for example, cheetahs, sea lions, fish and frogs) may have limitations, they strongly suggest that diversity matters, and their results are consistent with experimental studies on freshwater crustaceans and social insects. however, several questions remain: ( ) does a diversity threshold exist? in other words, can parasites be eliminated by increasing host genetic diversity above some threshold value? ( ) what are the relative effects of host density and host genetic diversity on disease spread? ( ) what are the effects of genetic diversity in the parasite population versus that of the host population? ( ) what is the heritability of parasite resistance in natural populations? very little is known about the heritability for resistance in natural populations. it should be high in populations where genetic diversity is maintained by parasite-mediated frequencydependent selection. these issues would be best addressed by data from natural populations. if parasites take hold or die out depending on how much host genetic diversity exists relative to the threshold, determining whether diversity thresholds exist in natural populations may have great value. this may be particularly helpful for conserving endangered species and mediating vector-human-parasite transmission. there were no data to deposit. figure the effect of increasing genetic diversity on r by adding new hosts. suppose we have hosts, with genotypes in equal frequency (point a). now suppose that we experimentally double the host population size, without affecting the genetic diversity (point b). we see an increase in r , but the increase is not large. now suppose we double the host population size, but also increase the number of genotypes from to (point c). we now see a large decrease in r , but it does not go below , so the disease can still spread. finally, suppose that we experimentally double the host population size, but we also increase the number of genotypes by fourfold (point d). now r not only deceases, but it goes below , so the disease will die out. redrawn from lively ( a). disease susceptibility in california sea lions infection genetics: gene-for-gene versus matching-alleles models and all points in between genetic diversity of daphnia magna populations enhances resistance to parasites rapid evolutionary dynamics and disease threats to biodiversity the invasion, persistence and spread of infectiousdiseases within animal and plant communities experimental variation in polyandry affects parasite loads and fitness in a bumble-bee unexpected consequences of polyandry for parasitism and fitness 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protection of susceptible potato cultivars against late blight in mixtures increases with decreasing disease pressure experimentally increased group diversity improves disease resistance in an ant species infection and colony variability in social insects parasites in social insects polygyny versus polyandry versus parasites queen promiscuity lowers disease within honeybee colonies parasites, pathogens, and polyandry in social hymenoptera parasites and the advantage of genetic variability within social insect colonies does inbreeding and loss of genetic diversity decrease disease resistance? the contribution of genetic diversity to the spread of infectious diseases in livestock populations genetic diversity within honeybee colonies prevents severe infections and promotes colony growth lower disease infections in honeybee (apis mellifera) colonies headed by polyandrous vs. monandrous queens disease and endangered species: the black-footed ferret as a recent example rapid anti-pathogen response in ant societies relies on high genetic diversity the costs and benefits of genetic heterogeneity in resistance against parasites in social insects disease ecology in the galapagos hawk (buteo galapagoensis): host genetic diversity, parasite load, and natural antibodies dioecy, hermaphrodites and pathogen load in plants how do pathogen evolution and host heterogeneity interact in disease emergence? genetic diversity and disease control in rice we thank c buser, l delph, l morran, and e rynkiewicz for comments on the manuscript. the authors acknowledge financial support from the national science foundation (deb- to cml and j jokela) and a royal society newton international fellowship (kck). cml also gratefully acknowledges a fellowship at the wissenschaftskolleg zu berlin during the construction of this paper. the authors declare no conflict of interest. key: cord- -mpv wegm authors: peng, kerui; safonova, yana; shugay, mikhail; popejoy, alice; rodriguez, oscar; breden, felix; brodin, petter; burkhardt, amanda m.; bustamante, carlos; cao-lormeau, van-mai; corcoran, martin m.; duffy, darragh; guajardo, macarena fuentes; fujita, ricardo; greiff, victor; jonsson, vanessa d.; liu, xiao; quintana-murci, lluis; rossetti, maura; xie, jianming; yaari, gur; zhang, wei; lees, william d.; khatri, purvesh; alachkar, houda; scheepers, cathrine; watson, corey t.; hedestam, gunilla b. karlsson; mangul, serghei title: diversity in immunogenomics: the value and the challenge date: - - journal: nan doi: nan sha: doc_id: cord_uid: mpv wegm with the recent advent of high-throughput sequencing technologies, and the associated new discoveries and developments, the fields of immunogenomics and adaptive immune receptor repertoire research are facing both opportunities and challenges. the majority of immunogenomics studies have been primarily conducted in cohorts of european ancestry, restricting the ability to detect and analyze variation in human adaptive immune responses across populations and limiting their applications. by leveraging biological and clinical heterogeneity across different populations in omics data and expanding the populations that are included in immunogenomics research, we can enhance our understanding of human adaptive immune responses, promote the development of effective diagnostics and treatments, and eventually advance precision medicine. analyses . this limits the discovery of genetic diversity contributing to mendelian diseases and to explore associations between genetic variants and trait variation across populations. in recent years, awareness has been increasing about the limited generalizability of findings across populations, motivating the inclusion of diverse, multiethnic populations in large-scale genomic studies , . for example, novel single nucleotide polymorphisms (snps) that are clinically associated with warfarin dosing were discovered in large scale genomics studies in individuals of african descent that had not been discovered in europeans , . whole-genome sequencing in individuals of african descent [ ] [ ] [ ] and whole-exome sequencing in a southern african population additional efforts have been made through international collaborations to establish reference genome datasets and recommendations for research in diverse populations; including the genomeasia k project, the human heredity and health in africa (h africa) initiative, and the clinical genome resource (clingen) ancestry and diversity working group (adwg) [ ] [ ] [ ] [ ] . khatri and colleagues discovered the -gene signature for diagnosis of tuberculosis based on transcriptome profiles of participants from countries , a finding that was generalized to patient populations from every inhabited continent in a span of years , . most importantly, the -gene signature has been clinically translated to the point-of-care test by cepheid . the inclusion of diverse populations in genomic studies has demonstrated benefits in the discovery and interpretation of gene-trait associations. similarly, greater diversity in immunogenomics research will enable the discovery of novel genetic traits associated with immune system phenotypes that are common across populations. broader inclusion of diverse populations may also enable researchers to address genetic heterogeneity in the context of translational research and clinical drug development, possibly revealing clinically relevant genomic signatures that are more prevalent in some populations than others. immunogenomics is a field in which genetic information at different levels of biological organization (epigenetics, transcriptomics, metabolomics, cells, tissues, and clinical data) has been characterized and utilized to understand the immune system and immune responses. here table ). rna-seq has traditionally been mapped to study entire cellular populations instead of amplifying at the specific regions. given the complexity of the tcr and bcr genomic loci, the accurate determination of germline immune receptor genes, from bulk rna-seq or whole-genome sequencing, has proved challenging . several computational methods show promise [ ] [ ] [ ] , but the mapping rate and accuracy remain to be improved. additionally, a wide-scale comparison is needed between results obtained from methods for deriving germline receptor genes from rnaseq studies, those obtained from established methods such as, targeted pcr and sequencing of genomic dna, the sequencing and assembly of bacterial artificial chromosome (bac) and fosmid clones , and those from more recent methods such as inference from airr-seq repertoires . many population genetic differences have been observed in genomics studies and immunogenomics is no exception [ ] [ ] [ ] . the current public databases of adaptive immune receptor germline genes are essential for airr-seq analysis and immunogenomics studies. however, the most widely used reference database for immunogenetics data, the international immunogenetics information system (imgt) , lacks a comprehensive set of human tcr and bcr alleles representing diverse populations worldwide. the same issue exists in hla databases: over % of rare hla variants from oceania and west asia populations were found to be absent in the genomes project panel . there is still more uncertainty due to the fact that descriptions of sample populations in databases are often self-identified based on geography or ethnicity, rather than genetic ancestry. however, progress has been made to address this issue in immunogenomics studies. for example, the airr community, an international community formed to promote high standard research in adaptive immune repertoire research, introduced the open germline receptor database (ogrdb) in september as a resource platform for germline gene discovery and validation from airr-seq data, to enrich the imgt database . collaborators in our team also created vdjbase, a platform for the inferred genotypes and haplotypes from airr-seq data . these efforts provide the opportunities to infer genetic ancestry. nevertheless, the majority of available germline sequences either lack population-level annotations or are biased toward samples of european descent. we argue that this shortcoming must be addressed through focused efforts that seek to include more diverse populations in immunogenomics research. as an interdisciplinary group, with expertise in biomedical and translational research, population biology, computational biology, and immunogenomics, we wish to raise awareness about the value of including diverse populations in airr-seq and immunogenetics research. in the areas of genetic disease research and cancer genomics, enhanced genetic diversity has led to demonstrable insights , . however, the field of immunogenomics has yet to benefit from a similar growth in diversity. at the current stage of the global covid- pandemic, numerous vaccine trials are underway in many countries worldwide, offering opportunities to investigate genetic factors in vaccine responses. yet, this will require careful clinical study designs that can effectively address confounding factors such as environmental and socio-economic differences. hiv- , zika , and sars cov- . we expect that vaccine and infection outcomes can also be shaped by genetic variability, including specific effects driven by immune-related genes . here, we make several recommendations for increasing diversity in immunogenomics research. first, we propose that the community should make a greater effort to include underrepresented populations in airr-seq and immunogenomics studies. already, those that have conducted airr-seq in populations of non-european descent have uncovered evidence for extensive germline diversity. for example, in a study of south african hiv patients, scheepers and colleagues discovered ighv alleles that were not represented in imgt . this promoted the hiv vaccine design by understanding the immunoglobulin heavy chain variable region (ighv) profile in the south african population. in a study in the papua new guinea population, one novel ighv gene and ighv allelic variants were identified from airr-seq data . these discoveries of novel alleles indicate the need to generate population-based airr-seq datasets. we do not recommend generalizing airr-seq findings to populations that are underrepresented in research, due to missing variation and lack of validation, which limits our ability to leverage airr-seq datasets in biomedical applications.therefore, increasing population diversity in immunogenomics studies can lead to improvements in a wide range of applications, including drug discovery and development, vaccine design and development. promoting precision medicine for underrepresented populations and improving predictions for treatment outcomes will become more feasible in the future with broader participation and inclusion. second, we argue that there are existing genomic datasets that could potentially be leveraged to augment ig/tcr germline databases, and inform the interpretation of airr-seq and immunogenomics studies across populations. extraction of population immunogenomics information from existing genomic datasets could be an effective strategy, as well as carefully embracing non-targeted sequencing data (eg. rna-seq) to focus on genetic diversity of samples. ancestry-associated genetic markers in short-read genome sequencing may help overcome the difficulties of relying on sample metadata in airr-seq datasets. this may also be time-efficient relative to waiting for the availability of sufficiently diverse airr-seq datasets. researchers have attempted to utilize paired-end rna-seq data in the cancer genome atlas (tcga) to infer the complementarity determining region (cdr ) of tumor-infiltrating t-cells , and to apply a computational method to rna-seq data in the genotype-tissue expression consortium (gtex) to profile immunoglobulin repertoires . similar ideas could be adapted to the direct prediction of allelic variants from short-read genomic sequence data , . however, challenges need to be overcome, including the high levels of copy number variation and segmental duplication in the bcr and tcr loci, and the need for protocols to validate novel allelic variants gleaned from short-read sequencing data , finally, we suggest the need for additional infrastructure and expertise in regions and countries with populations underrepresented in research, and to enhance collaborations between countries, which are critical in minimizing global health disparities. online training sessions that are customized for conducting immunogenomics research in diverse populations would be beneficial to the biomedical community, perhaps especially in those regions. the content of these trainings might include participant recruitment strategies with a commitment to outreach and education to increase participation, sample collection methods, steps to running sequence experiments onsite or in collaboration with other academic institutions or commercial companies, uploading sequencing data to appropriate repositories, and performing bioinformatics analyses. virtual learning platforms for bioinformaticians have been established by members in our group, and these could be leveraged to provide such trainings . our interdisciplinary group consists of leading researchers from countries, including the us, canada, norway, france, sweden, russia, the uk, israel, china, south africa, chile, peru, and french polynesia. we share concerns about the lack of diversity in immunogenomics and embrace the need for engaging our combined efforts to tackle this challenge. to spearhead the enterprise of fostering diversity in the field, we have formed this task force with the aim of developing a global consortium on diversity in immunogenomics. this consortium will seek to promote inclusive, international, and interdisciplinary research, supported by transparent and 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receptor genotype and haplotype database williams-beuren syndrome in diverse populations whole-genome sequencing reveals elevated tumor mutational burden and initiating driver mutations in african men with treatment-naïve, high-risk prostate cancer & the covid- host genetics initiative. the covid- host genetics initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the sars-cov- virus pandemic genomewide association study of severe covid- with respiratory failure identification of a cd -binding-site antibody to hiv that evolved near-pan neutralization breadth recurrent potent human neutralizing antibodies to zika virus in brazil and mexico structural basis of a shared antibody response to sars-cov- landscape of tumor-infiltrating t cell repertoire of human cancers worldwide genetic variation of the ighv and trbv immune receptor gene families in humans correction: a database of human immune receptor alleles recovered from population sequencing data comment on 'a database of human immune receptor alleles recovered from population sequencing data living in an adaptive world: genomic dissection of the genus homo and its immune response how bioinformatics and open data can boost basic science in countries and universities with limited resources diseases of the national institutes of health under award number u ai .we thank dr. nicky mulder for the valuable comments that greatly improved the manuscript. key: cord- -qpufvt o authors: neufeld, zoltan; khataee, hamid; czirok, andras title: targeted adaptive isolation strategy for covid- pandemic date: - - journal: infect dis model doi: . /j.idm. . . sha: doc_id: cord_uid: qpufvt o we investigate the effects of social distancing in controlling the impact of the covid- epidemic using a simple susceptible-infected-removed epidemic model. we show that an alternative or complementary approach based on targeted isolation of the vulnerable sub-population may provide a more efficient and robust strategy at a lower economic and social cost within a shorter timeframe resulting in a collectively immune population. we consider the standard susceptible-infected-removed/recovered (sir) epidemic model [ ? ] to represent the current covid- pandemic: where the parameter k characterises the probability of transmission of infection from the infected (i) to the susceptible (s) fraction of the population, and γ is the rate of recovery, which is assumed to lead to immunity or death (r). the behavior of the model depends on a single non-dimensional parameter r = k/γ which is the number of new infections caused by a single infected in a fully susceptible population. the condition for an epidemic outbreak is r > , otherwise the infection dies out monotonously. typical estimates of r for the covid- epidemic are roughly in the range − . [ ] [ ] [ ] . we will use γ = . day − consistent with a typical recovery time of around − weeks [ ] [ ] [ ] . a few example solutions of the model in equations ( ) for different values of r are shown in fig. (a,b) . since the large majority of the covid- infected population develops very mild or no symptoms, transmission cannot be eliminated by detecting and isolating symptomatic covid- patients. the so called "social distancing" strategy aims to reduce social interactions within the population decreasing the probability of transmission of the infection, represented by the parameter k in the model. a strong reduction of social interactions may thus lead to r < when the infection dies out, as i(t) ∼ exp(−γ( − r )t). if the reduced r is still larger than unity, the result is a smaller epidemic outbreak, with a lower peak value for the infected fraction, and a reduced number of cumulative infections: i total = − s(∞), where s(∞) is the susceptible fraction at the end of the epidemic. the total infected population is the solution of the transcendental equation: ln( − i total ) + r i total = ( fig. d) . a side effect of this reduction, however, is that the duration of the epidemic outbreak increases significantly. the dependence of the peak infected fraction and the time to reach maximum infection are shown in fig. (c). for example, starting with a reference value r = . , the time to peak infection is around days. reducing r to . , extends the time to peak infection to ∼ days, while the maximum infected fraction is reduced from ∼ % to ∼ . % and the total infected by the end of the epidemic decreases from ∼ % to ∼ %. decreasing r by social distancing reduces the total infections and the peak infected fraction, which is critical due to limited hospital capacity, but it has the following possible drawbacks: • if r remains > , the social distancing can significantly extend the duration of the epidemic, making it difficult to maintain the reduced transmission rate over a long time period in a large population. • perhaps the most important problem is that there is no clear exit strategy until large scale vaccination becomes available. since at the end of the epidemic a large proportion of the population remains susceptible to infection, after relaxation of social distancing, the population is highly susceptible to recurrent epidemic outbreaks potentially triggered by remaining undetected or newly imported infections from other regions/countries where the infection has not been eliminated yet. • social distancing measures over extended period of time applied uniformly to a large population lead to widespread disruption of the functioning of the society and economy therefore it has a huge long term cost. to address these issues, we consider an alternative or complementary strategy. an essential feature of the covid- infections is that it produces relatively mild symptoms in the majority of the population, while it can also lead to serious respiratory problems mainly in the older population (> years of age), or in individuals with pre-existing chronic diseases [ ] . for example, the hospitalization rate of the symptomatic cases in the − age group is . % out of which % requires critical care and . % of the infections lead to death [ ] . in contrast, for the − age group hospitalization rate is . % out of which . % is critical and the fatality ratio of the infected is . %. although the transition between these extremes is gradual, a fairly sharp transition takes place around the age of . in addition to age, pre-existing chronic diseases is an additional criteria for identifying a vulnerable group in the population. based on the limited currently available data around − % of deaths due to covid- already had underlying chronic diseases, which is of course very common in the older age groups. to take into account the markedly different age-dependent outcome of the covid- infection, we extend the standard sir model by separating the population into two compartments: the lowrisk majority population with mild symptoms, and a vulnerable, mainly older population, where infection is more likely to lead to hospitalization and death; see fig. (a). properties of such multi-compartment epidemic models have been studied previously in [ , , ] . the dynamics of the two-compartment sir model is described by the equations: where f v is the vulnerable fraction and µ is a non-dimensional parameter of a targeted isolation of the high-risk group, and µ = means that there is no isolation everyone mixes the same way. numerical simulations of this model are shown in fig. . when we neglect new infections caused by the vulnerable group, the majority population follows the same sir dynamics in equations ( ) as described above independently of the vulnerable population. then the infection rate of the vulnerable population is described by: where µ represents the rate of transmission from the low-risk infected population (i) to vulnerable susceptible (s v ). thus, the relative proportion of newly infected vulnerable individuals (requiring hospitalization with possibility of death) per unit time is determined by the product µk( −f v )i(t). we can also calculate the proportion of the vulnerable population infected over the whole course of the epidemic as: where the total infected fraction of the low-risk population, i total , is determined by r through the standard sir dynamics as shown in fig. (d) . the validity of this approximation is comfirmed by comparison to numerical simulation of the full two-group model; see fig. (b). reducing the loss in s v requires reducing the exponent in equation ( ) . while social distancing aims to reduce the total infected population by decreasing r , an alternative or complementary approach focuses resources to shield the vulnerable population. this could be achieved by targeted measures: restricting mobility, providing free home-delivery of food and medication, increased support addressing communication and healthcare needs, and providing separated living space where needed. since the isolation strategy targets a sub-population, a radical isolation is likely to be more effective than uniform social distancing, and at a smaller cost for the economy and for the general functioning of the society. the two-group sir model helps to evaluate such strategies by representing the exposure of the vulnerable population by the parameter µ. complete isolation and lack of specific isolation efforts correspond to µ = and µ = , respectively. the overall fatality of the pandemic is primarily driven by the size of the infected vulnerable population, r v (∞) = s v ( ) − s v (∞) shown in the contour plot in fig. (d) . social distancing reduces r (horizontal arrow), while isolation of the vulnerable population changes the parameter µ (vertical arrow). depending on the epidemiological situation, the public response should be a mixture of the two efforts. however, social distancing may extend the duration of the epidemic (which may affect the sustainability of efficient isolation) and results in insufficient overall immunity of the majority population against a recurrence of the epidemic outbreak. the targeted intervention likely allows a more substantial reduction in µ, and hence in the total size of the infected vulnerable population. with limited resources available, when the strategy is primarily based on drastic targeted isolation over a shorter time, the end result is a collectively immune population resistant to further infections ("herd immunity"). it is also apparent that the integral in equation ( ) can be reduced by decreasing µ in a timedependent manner. this kind of adaptive measure can be implemented by monitoring the progression of the infection i(t) via statistically representative testing of different regions and cities, and intensifying/relaxing the isolation of the vulnerable population accordingly. let us consider the case when the low-risk population is ∼ − % of the total, and when infected % is hospitalized, with . % requiring intensive care [ ] . assuming that the intensive care capacity is around - per , this allows for ∼ % infected at the peak of the epidemic in the low risk population, as % × % × . % = per . an infection peak of % corresponds to r ∼ . (fig. b) . by the end of the epidemic, this results in i total ∼ . within the low-risk population (fig. d ) so that the immunity in the total population is ( − f v ) × . ≈ %. assuming that after the epidemic the transmission rate increases back to r = . , the minimum immune fraction needed for herd immunity is around %. therefore, relaxing social distancing should happen before the end of isolation to allow for further increase of the immune proportion in the low-risk group and to avoid the spread of infections into the high-risk population. our model and conclusions rely on the separation of the population based on age and health into two compartments with very different outcomes and applying differentiated protective measures to a minority high-risk group while allowing for the development of immunity in the rest of the population. at the time of writing, certain countries follow various combinations of social distancing and isolation. in sweden, only moderate social distancing is implemented which will likely lead to development of immunity in the population. this strategy, however, without introducing efficient targeted measures to protect the vulnerable population may lead to high mortality and oversaturation of the health care system. italy and spain, on the other hand, implemented severe social distancing, but so far this seems to be unable to stop the progress of the epidemic and may in fact be on track towards achieving large scale infection and immunity in the population. however, with too much focus on the implementation of uniform social distancing and no clear targeted measures for identifying and efficiently protecting the vulnerable sub-population can lead to a scenario with high mortality in spite of the high social and economic costs of an extended and potentially recurrent epidemic. another interesting observation is the striking difference between the mortality within the confirmed infected patients in italy (∼ %) compared to germany (∼ %). while there can be multiple reasons for this difference, it is possible that the closer social and family interactions between the older and younger generations in italy, indicates a higher baseline value of µ, and/or the current exposure of the disease targets mainly the younger population in germany with policies in place to decrease the exposure of the vulnerable population. we declare that we have no conflict of interest of any kind in relation to the research described in this manuscript. on behalf of the authors, (zoltan neufeld, hamid khataee and andras czirok) zoltan neufeld population biology of infectious diseases: part i a contribution to the mathematical theory of epidemics early dynamics of transmission and control of covid- : a mathematical modelling study unique epidemiological and clinical features of the emerging novel coronavirus pneumonia (covid- ) implicate special control measures review of the clinical characteristics of coronavirus disease (covid- ) clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study impact of non-pharmaceutical interventions (npis) to reduce covid mortality and healthcare demand the type-reproduction number t in models for infectious disease control final size of an epidemic for a two-group sir model a new approach for designing disease intervention strategies in metapopulation models key: cord- -rrwy osd authors: neiderud, carl-johan title: how urbanization affects the epidemiology of emerging infectious diseases date: - - journal: infect ecol epidemiol doi: . /iee.v . sha: doc_id: cord_uid: rrwy osd the world is becoming more urban every day, and the process has been ongoing since the industrial revolution in the th century. the united nations now estimates that . billion people live in urban centres. the rapid influx of residents is however not universal and the developed countries are already urban, but the big rise in urban population in the next years is expected to be in asia and africa. urbanization leads to many challenges for global health and the epidemiology of infectious diseases. new megacities can be incubators for new epidemics, and zoonotic diseases can spread in a more rapid manner and become worldwide threats. adequate city planning and surveillance can be powerful tools to improve the global health and decrease the burden of communicable diseases. t he industrial revolution in the th century led to larger cities with greater potential for growth and development both for the individual and the community. living in a city can provide you with several advantages, such as the possibility for higher education, a new job with higher income, the security of better health care, and the safety of social services. in , the united nations estimated that % of the world's population, . billion, lived in urban centres ( ) . economic growth for countries has been linked to urbanization and countries with high per capita income are among the most urbanized, whereas countries with low per capita income are the least urbanized ( ) . the financial and political power is often concentrated in the cities, which leads to unique possibilities for action and quick response if needed. the process of urbanization refers to increased movement and settling of people in urban surroundings ( ) . however, the meaning of the word 'urban' does not have a universal definition. a wide variety of different interpretations can be found in various countries, and often they do not share the same understanding. different versions could be: living in the capital, economic activities in the region, population size, or even density. the lack of a universal definition makes it hard to compare different countries and cities in regard to public health and the burden and impact of infectious diseases ( ) . many of the studies conducted address the differences between urban and rural areas, and do not compare different urban settings. it can thus be difficult to get a global overview and get a better understanding of the burden of infectious diseases in these specific environments. cities from around the world can also be very heterogeneous and the local diseases and health challenges can greatly differ. the challenges for one city can be completely different for another location ( ) . about a century ago, only % of the world's population lived in cities, and in the least developed countries the percentage was only % ( ) . approximately half of the world's population now live in these urban centres. the two inhabited continents, which currently are the least urbanized, are asia and africa, with respectively and % of the population living in cities. these percentages are expected to rise dramatically by the year to and % respectively ( ) . in the last decade, the growth in the urban population has been the highest in asia, adding . million urban migrants per week. africa was the second highest contributor with . million. the total figure of new urban residents per week during the last decade was on average . million. it is in africa and asia where the current rapid growth is taking place. years are that almost all of the population growth will be in urban areas, but the growth in developed countries is expected to remain largely unchanged ( ) . chronic illnesses have been increasing in importance for the developing world. worldwide the leading causes of death in were ischaemic heart disease followed by stroke, lower respiratory infections, chronic obstructive lung disease, and diarrhoeal diseases. however, if you look at the list for low-income countries, infectious diseases still have a profound impact. the top three causes of death in these settings are all infectious diseases: lower respiratory infections, hiv/aids, and diarrhoeal diseases ( ) . many of the lower income countries are expected to have a major growth among the urban population, which leads to considerable challenges for the governments and health care to keep up to pace and develop their social services and health care as these regions grow. the rise of the new modern cities also creates potential risks and challenges in the aspect of emerging infectious diseases. different risk factors in the urban environment can, for example, be poor housing which can lead to proliferation of insect and rodent vector diseases and geohelminthiases. this is connected to inadequate water supplies as well as sanitation and waste management. all contribute to a favourable setting for both different rodents and insects which carry pathogens and soil-transmitted helminth infections. if buildings lack effective fuel and ventilation systems, respiratory tract infections can also be acquired. contaminated water can spread disease, as can poor food storage and preparation, due to microbial toxins and zoonoses ( ) . the density of inhabitants and the close contact between people in urban areas are potential hot spots for rapid spread of merging infectious diseases such as severe acute respiratory syndrome (sars) and the avian flu. criteria for a worldwide pandemic could be met in urban centres, which could develop into a worldwide health crisis ( ) . adequate city planning can be a key factor for better overall health, and such considerations must be in the mind of the governing bodies. today's megacities are very heterogeneous with large slum settlements, which lead to challenges for overall health and health care in the community. within one large urban setting, there can be huge differences in health conditions depending on where you live. in general, the urban health is better, but in some areas, it can actually be worse compared to certain rural environments ( ) . of the estimated billion people living in urban centres, about one-third live in slum areas ( ) . the ever-changing environment of cities has made certain infectious diseases both emerge and re-emerge. pathogens which adapt to urban environments from rural settings can spread in a more rapid manner, and be a greater burden to the health care services ( ) . this review article examines the urban world and how the current rapid urbanization around the world is affecting the epidemiology of emerging infectious diseases. currently the most rapid growth in urban population is taking place in the developing countries, and poses many different challenges compared to traditional highincome countries. this review focuses on these growing regions and their implications and how emerging infectious diseases affect the community. urban population Á a heterogeneous group with different living conditions cities around the world can look very different if you compare the living conditions for the residents. however, it is not only different cities that can have completely diverse standards of infrastructure and social security. the same city can provide very varying conditions for their residents. living in the slums compared to more wealthy neighbourhoods, will expose the inhabitants to different risks. traditionally cities can offer many advantages compared to rural settings, but under certain circumstances they can rather be a health hazard. the rapid migrations of people to cities can lead to overcrowding, which can generate slums or shanty towns. these slums are characterized by poor housing, lack of fresh water, and bad sanitation facilities ( ) . all of these shortages can be a threat to the residents' health and be a possible breeding ground for infectious diseases. the location of slums are often outside of the city centres, in more hazardous locations and the population feels a lack of social and economic opportunities compared with other residents. in sub-saharan africa, % of the urban population in lived in shanty towns ( ) . for example, in , % of the urban population in central african republic lived in these slums ( ) . in kenya's capital nairobi, % of the population lives in slums, and child mortality there is . times greater than other parts of the city ( ). the community and health care services have great challenges to provide the entire population with equal and adequate service. the collected parties need to be aware of the differences in threats with respect to infectious diseases, both at the local and governmental levels. certain infectious diseases have been shown to be more widespread in the slums. an example of this is the diarrhoeal disease cholera. infections have been linked to slums in dar es salaam, tanzania, with high population density and low income ( ) . in several other countries, cholera incidence is the highest in urban regions with high population density ( , ) . differences in prevalence of asymptomatic carriers of antimicrobial drug-resistant diarrhoeagenic escherichia coli have also been found in brazil between slum settlements and more wealthy parts of the community ). the poor infrastructure in the slum can be a barrier for improvement, but at the same time targeted interventions for safer water and better sanitation carl-johan neiderud facilities could potentially have a profound effect of the overall health. overcrowded housing in high-density populations in the slums can be a breeding ground for infectious diseases such as tuberculosis. the rate of tuberculosis has traditionally been higher in urban centres compared to rural ( , ) . studies in slum settlements in dhaka city, bangladesh, indicate a high prevalence of tuberculosis, which was almost twice as high compared to the overall national average and four times higher than the overall urban levels ( ) . however, different patterns can be seen in different countries; for example, in poland the rates of tuberculosis have shown only slightly lower incidence in rural population compared to urban, . per , versus . per , respectively ( ) . tuberculosis in the united states has declined in the twentieth century, and several factors such as improved nutrition status, socioeconomic status, overall public health, and new drug regimens have been thought to play a major role. however, in the mid- s a resurgence occurred which reached its peak in , especially in urban areas among the homeless and incarcerated population ( ) . the knowledge regarding symptoms, transmission, and prevention has been shown to be greater among the urban population in pakistan's punjab province compared to the rural population. health-seeking behaviour was also better among the urban population, in the aspect of when to seek medical advice for early diagnosis and potential treatment ( ) . information about infectious diseases and how they spread in the community can help the individuals to protect themselves, but knowledge about the slums and the infectious diseases panorama is also crucial for local physicians. they need to know how to look for the correct diagnosis, even if their diagnostic tools might be limited. the right hypothesis from the start in these cases is even more important. the rapid urbanization around the world leads to great challenges in city planning. the rapid influx of migrants can lead to overcrowding and local governments might not be able to provide safe housing, drinking water, and adequate sewage facilities, all of which are potential health hazards and must be taken into account for safe city planning. today more than half of the world's population, almost billion people, have access to piped water connected to their homes. since , well over billion people have gained improved drinking water facilities, and almost billion people have access to improved sanitation. however, more than million people still lack access to improved sources of safe drinking water, and in sub-saharan africa half of the population lack such facilities. globally the decline of open defecation between and went from to %. however, billion people in the world still practice open defecation. in this group, % live in rural areas, but the actual amount of residents from urban settings is gradually increasing. between and , the group in urban settings which lacked sanitation actually significantly increased from million to million, which could be explained by population growth ( ). much of the hard work to improve sanitation facilities has benefited large population groups, but the rapid influx of new urban residents shows that there is still much hard work to be done. residents who are subject to overcrowding and who lack access to safe drinking water or proper sanitation can be more susceptible to soil-transmitted helminths ( ) . these infections are among the most important causes of physical and intellectual growth retardation in the world and have a major impact on public health ( ) . good hygiene practices and good sanitary conditions have lowered the prevalent levels of contamination. in the brazilian city of salvador, with a population of . million, an improvement of sewerage coverage from to % of the households led to an estimated overall reduction of diarrhoeal diseases of % ( ) . neglected tropical diseases can cause substantial health problems in developing countries, and some of these diseases have a faecal-oral transmission pathway. examples of such diseases could be schistosomiasis, trachoma, and soiltransmitted helminthiases. improved sanitation could contribute to a significant improvement for the public health. in many countries, however, the focus is on treatment by medication and not improved sanitation. the reason could be that it would be much more expensive to carry out the necessary infrastructural improvements ( ) . safe drinking water and proper sanitary facilities must be taken into account in city planning. factors like this can potentially have a profound positive effect in lowering infectious diseases with a faecalÁoral route. however, the real challenge lies in the uncontrolled growth of slum settlements. poor housing and overcrowding can also contribute to vector proliferation. one example of this is for chagas disease, which is a parasitic infection caused by the protozoan trypanosoma cruzi. an important mode of transmission is vectorial infected bites of triatomine bugs. living in close contact to domestic animals and poor hygienic habits have also been identified as risk factors ( ) . chagas disease affects an estimated million people every year, and is an important health challenge in latin america. in recent decades, progress has been made to reduce the burden of disease, by vector control, screening blood donors, improved housing, and epidemiological surveillance. chagas disease is a growing health problem in non-endemic areas because of population movements ( ) . it is estimated that , individuals in the united states are infected ( ) and the most affected country in europe, spain, is thought to have , Á , cases ( ) . the example of chagas disease shows that physicians who practice in countries where the disease is not present must be aware of the travel history of the patient to connect the potential symptoms to the correct diagnosis. the environment in urban cities has proven to be favourable for the rat population (rattus spp.) and close encounters between rats and humans can lead to transmission of zoonotic infectious diseases. they can carry pathogens such as yersinia pestis, leptospira spp., rickettsia typhi, streptobacillus moniliformis, bartonella spp., seoul hantavirus, and angiostrogylus cantonensis ( ) . new york city has one of the largest populations of rats in the united states. it has been shown that encounters between rats and humans have been linked to proximity to open public spaces and subway lines, the presence of vacant housing units, and low education of the population ( ) . information like this can be useful for health officials when they launch specific control initiatives. the changes in human population with increased urbanization and urban poverty has also altered our perception of some zoonoses linked to the rat population. leptospirosis has traditionally been perceived as a primarily rural disease, but the incidence in urban centres is increasing ( , ) . in chinese cities, the incidence of seoul hantavirus haemorrhagic fever with renal syndrome has been linked to urban growth, growing rat population, and increase ratÁhuman contact ( ) . large megacities all over the world have large rat populations, but the surveillance and local knowledge seem to be inadequate. a better understanding of how to prevent uncontrolled growth in rat population can potentially lead to a decline of these zoonotic diseases. the growing trend of urbanization around the world has shifted some infectious diseases, which have traditionally been perceived as rural, to urban settings. the world health organization (who) has published a list of neglected tropical diseases. several of them have now become a reality in the urban environment, these diseases are something the practicing physicians in these areas have to be aware of ( ) . many of the diseases on the list are present in the developing world, which sometimes lack the opportunity to solve these problems by themselves. these countries need help from the global community. one of the neglected infectious diseases is lymphatic filariasis (lf) with billion people at risk, and . million in urban areas. one of the main reasons is the lack of proper sanitation facilities ( ) . lf still has its major impact in rural settings, but the increasing urbanization in the developing world has made lf an infectious disease that also has to be considered elsewhere. one of the parasite species wuchereria bancrofti has been located in many urban areas and has the potential for transmission in this environment. moreover, one of the vectors for the parasite is the mosquito culex quinquefasciatus, which thrives in these surroundings, especially in overcrowded areas with poor sanitary and draining facilities. however, within one city the transmission can vary substantially depending on the standard of the sanitary conditions. the mosquito vector culex spp. can be found in large parts of central and south america, east africa, and asia ( ) . another vector which has adapted to urban surroundings is the mosquito aedes aegypti, which is a key component for dengue transmission. dengue is on who's list of neglected tropical diseases, and is on the rise worldwide. the number of infections has drastically increased in the tropical regions of the world in the last years. recent studies have estimated million cases each year, and the burden is the highest in india with onethird of all the new infections ( ) . several factors have played a big role in the escalation, such as urbanization, globalization, and lack of mosquito control. aedes aegypti lay their eggs in artificial water containers made by humans, which is a key component in the urban transmission cycle. the adaption of dengue through its vector has made dengue an infectious disease on the clear rise ( ) . thailand is a country with all four serotypes of dengue virus, and the epidemics of dengue haemorrhagic fever have shown a possible correlation to originate from the urban capital of bangkok and then spread geographically in an outward manner to more rural settlements and provinces. a model to understand this mechanism could lead to more effective use of the health systems in the affected areas ( ) . dengue has become a global problem and is no longer restricted to the developing world. despite better knowledge, it seems tough to control the vector, which has adapted to the urban environment and living close to people. an efficient vaccine is not yet commercially available, but could be a powerful factor in the fight against the global dengue epidemic. often several different factors need to be favourable for a vector-borne disease to adapt to the conditions in an urban environment. for example, west nile virus (wnv) infection is an infectious disease which has become a reality in the urban environment. the primary vector is the mosquito culex pipens, which lay their eggs in water resources which are often man-made. however, for a successful transmission cycle wnv also need the american robin (turdus migratorius), which has several broods per season and hatchlings are more susceptible to wnv infection than adult birds ( ) . the county of dallas, texas, experienced an epidemic of wnv infections in . surveillance reports revealed % of the cases in the united states were found in dallas county ( ) . it shows for a vector-borne disease to have a successful transmission cycle several different factors need to be in place to affect the human population. leishmaniasis is a disease caused by the protozoa leishmania, which affects million and threatens million people in different countries. there can be different clinical presentations such as cutaneous and visceral ( ) . leishmaniasis is transmitted by the vector phebotomine sandflies. when rural migrants bring their domesticated animals to urban settings, often slums, they create favourable conditions for an urban transmission ( ) . it has been shown that it is a growing health problem and the ongoing urbanization has contributed to the increase ( ) . if the different vectors can adapt to the urban environment and man-made resources, the potential health implications can be of major concern. control programs and adequate surveillance is of importance, but in rapidly growing cities and slums it can be tough to implement such measures. emerging infectious diseases can also make the jump to stable transmission in the urban surroundings and surveillance of these can potentially prevent major health concerns and high cost for the health care services. who can play a major role in the fight for better control and knowledge. many of the countries in the developing world do not have the proper resources and the problem is not concentrated to one region, but is a global concern. numerous of the neglected tropical diseases play a major role in the developing world, which is currently experiencing a much faster pace of urbanization compared to the developed world. the who's call for help is important and, for example, dengue is now turning into a global crisis. safe and targeted assistance can be a huge factor for overall health; such assistance could be an effective vaccine or safe and easy vector control programs. urban centres can be catalysts for rapid spread of infectious diseases. the basis of large population groups in a restricted area can provide the perfect conditions for different epidemics. international travel has connected the world in the last century, and this mobility creates a potential threat of many emerging diseases. international tourist arrivals have shown an exceptional growth from million in to , million in . according to the latest forecast from the world tourism organization, international tourism arrivals will continue to increase, and in the figure is expected to be . billion ( ) . with the pace of modern travel, highly contagious infectious diseases can be a potential threat in a completely different setting compared to the original outbreak. urban population and the density of residents can meet the criteria for a new epidemic and create a public health disaster, if not taken seriously. international trade and travel can potentially also contribute to the occurrence of a worldwide pandemic. sars emerged as a global threat in . sars is thought to originate from the sars-like coronavirus (scov) of bats and reached the human host in china due to hunting and trading of bats for food ( ) . the disease was first recognized in wildlife markets in guandong, china. investigations have found this scov from the himalayan palm civets in live-animal markets in the region. the first cases of sars reportedly occurred in individuals who handled these animals to prepare exotic food, and the virus is thought to have crossed over to their human host ( ) . sars could then spread throughout the world by, for example, international travel. it spread in urban dwellings in large cities and in wellequipped city hospitals. public fear of travelling led to considerable economic losses that affected entire countries ( ) . the example of sars shows that food markets in southern china can be the origin of a worldwide health crisis. travel routes around the world have connected the urban world and large megacities like never before. accordingly it is important to take necessary preventive measures before the epidemic gets out of control, and here big organizations like who, but also governments, play an important role. early action is of utmost importance, and functional surveillance programs needs to be in place. the zoonotic disease dengue is endemic in most tropical and subtropical regions, which often are also popular tourist destinations. travellers to endemic countries can contribute to the spread of the disease. the burden of disease is on the rise, and estimations are that in returning travellers from southeast asia, dengue is now a more frequent cause of febrile illness compared to malaria ( ) . dengue is now an urban health problem, which is one of the major reasons why the rise is exceptional. the global rising problem of antibiotic resistance has also been linked to international travel. the worldwide spread of certain antibiotic resistant staphylococcus aureus has been linked to tourism, which shows the potential impact on international health ( , ) . faecal colonization with esbl-producing enterobacteriaceae has also been linked to international travellers in several studies ( Á ). the physician needs to take into account the recent travel activities of the patient to better evaluate the current condition and need for potential treatment and care. global travel shows no signs of decline and the interconnected megacities around the world make global surveillance even more important when it comes to contagious infectious diseases. measurements to stop the spread need to be taken at the original location, but knowledge about the specific disease needs to be passed on to the global community and local health workers in other parts of the world. this global surveillance and alert system needs to be fast and efficient to, if possible, reduce the impact. the expected rise of travel makes it critical for the future global health and the possibility to react in time for possible threats. zoonotic disease a challenge for the future rapid and sometimes uncontrolled urbanization can, in certain circumstances, lead to closer encounters with wildlife. human influence on the ecosystems creates meeting points for new and potential zoonotic diseases, which could have a profound impact for both local and global health. the global trends of urbanization push people to previously untouched ecosystems. new housing in the outskirts of big cities can potentially be meeting points for new and already known zoonotic diseases. of emerging infectious diseases, which have been recognized between and , more than % have been zoonotic diseases ( ) . living in close contact to domesticated animals and hunt for 'bush-meat' can also be risk factors for an infectious disease to make the jump from the animal host to humans. major deforestation creates closer contact between humans and bats and even primates, who can potentially be host for 'new' viruses. a better understanding, surveillance, and prevention of zoonotic diseases would be of great value, to both prevent and manage this upcoming threat for global health. hot spots for this transmission have been found and they often correlate where the process of urbanization is on the clear rise ( ) . even if it is not always the urban population who is at the front of new encounters with wildlife, it can still have an effect on urban health. the trend of people moving to cities are at the highest, where many of these new encounters with ecosystems take place, and infectious diseases can be introduced to these growing urban environments. the sometimes uncontrolled growth of cities pushes residents to untouched ecosystems when new housing expands. ebola virus disease (evd) has had a profound impact on the world in . since the spring of , the world has witnessed an unprecedented epidemic of this zoonotic disease. the hub of the epidemic has been the three countries in western africa: sierra leone, liberia, and guinea. it all began in december in guinea, in the providence of guéckédou, in the eastern rainforest region. the disease transmission in the capital of conakry is thought to be the first major urban setting for evd ( ) . who was first notified of the evd outbreak in march , and on august , the who declared the current situation as 'public health emergency of international concern' ( ). before, evd outbreaks in central africa had been limited in size and geographical spread to a few hundred persons, mostly in remote areas and not large urban settings ( ) . the centre of the epidemic (guinea, liberia, and sierra leone) has, as many of their neighbouring countries, a large population living in rural settings; only , , and % of their population live in urban centres ( Á ). the population is, however, highly interconnected in these countries with travel and crossborder traffic, with good road access between rural and urban settings. these communications have made the magnitude of the evd epidemic possible. despite cases of evd in nigeria and lagos, a megacity with million inhabitants, the transmission has been limited, which proves that implementation of control measures can limit the transmission ( ) . the mortality rate has been high in previous outbreaks, up to % ( ) . the fatality rate in the west africa epidemic has been estimated to around % for guinea, liberia, and sierra leone when data for patients with recorded definitive clinical outcomes ( ) . this unprecedented epidemic points out the importance of better surveillance, understanding, and preventions measures for this potentially deadly virus. ebola virus (ebov) is thought to be a zoonotic disease, and fruit bats are under investigation to be the natural reservoir. ebov sequences have been found in these animals near the human outbreaks which implies where the virus might originate from ( , ) . closer contact with humans and fruit bats are thus risks for a new global health crisis and the severity of an ebola epidemic has already been witnessed. the high costs, both from an economic and overall health perspective, have affected entire countries and have even cost lives on the other side of the earth. urban centres offer their residents greater possibility for health and social services. different factors, such as education, direct primary care services, and the governments' capacity for rapid response to upcoming health threats, can contribute to the opportunities in a city. however, in many cities the poor can find it difficult to access proper health care, due to the cost of such services. in more rural areas, the problem can instead be the distance to the nearest clinic, which in reality makes it impossible for prompt and efficient treatment ( ) . malaria has historically been and is still a major health concern in large parts of the world. who estimates million cases ( Á million) of malaria and , deaths ( , Á , ) in . the highest mortality rates have been shown to be closely linked to poor countries with a low gross national income (gni) per capita ( ) . estimations have been made that nearly % of the total african population, million, currently live in urban settings where malaria transmission is a reality. the annual incidence is estimated at . Á . million cases of clinical malaria among the urban population in africa ( ) . the relationship between the malaria mosquito vector and the human host determines the burden of morbidity and mortality. this interface is dependent on many different factors and the degree of urbanization is an important one. a significant reduction in malaria transmission has been observed over the last century. increased urbanization and decreased transmission have correlated in several different studies ( ) . however, whether it was the increased urbanization that led to a reduction in transmission or the malaria reduction that led to development that promoted urbanization of societies is a challenge to determine ( ) . a clear connection has been shown between reduced transmission of plasmodium falciparum and urbanization; however, for plasmodium vivax it is less obvious. for p. vivax, a connection has been found globally and in asia and africa; inconsistent results, however, were found in the americas. several possibilities could explain these incoherent results, such as more widespread transmission of p. vivax, lower transmission intensity, the wide distribution in asia, and high prevalence of duffy negativity in africa, which protects against p. vivax ( ). the overall decrease of the burden of malaria has been a positive effect of urbanization, but the exact mechanisms are not yet known. however, it seems that urbanization can have a favourable influence. immunization status between residents in urban centres and rural areas can differ. coverage of measles vaccination in indonesia have shown to be . % in rural areas, compared with . % in urban regions ( ) . studies in nigeria have shown that sometimes the coverage can actually be better in more rural areas, and it might be explained by better mobilization and participation in the delivery of immunization services ( ) . in a study in uganda, % of the urban group compared to % in the rural areas were fully immunized, but polio vaccine was given to % in the urban group and % in the rural group ( ) . immunization coverage can also vary considerably among different settings, not only between rural and urban surroundings, but also between urban, rural, and slum settlements. in changdigarh, a union territory of india, full immunization of children at the age of was % in slums, % in urban, and . % in rural settings ( ) . it shows that there can be a wide variety of reasons for immunization status among the population in different regions and countries of the world. effective immunization can be a cost-effective measure in poorer countries. high coverage can prevent epidemics in large cities and save many lives; however, immunization needs to be available both for the rural and urban population to achieve the greatest benefit. a study in tanzania has compared the knowledge about certain zoonotic diseases among general practitioners in urban and rural areas. the rural practitioners had poor knowledge of how sleeping sickness is transmitted and clinical features of anthrax and rabies. laboratories in rural areas are often poorly equipped and cannot always diagnose certain zoonotic diseases, which could limit the doctors' capability for correct diagnosis and treatment ( ) . public knowledge about certain infectious diseases can also vary depending on many different factors. the knowledge about sexually transmitted diseases (stis) among bangladeshi adolescents was higher among people in urban areas compared to rural, both in general and hiv and aids ( ) . the same results about hiv and aids have been found among a canadian population ( ) . studies in chengdu and shanghai, china, have shown risk perception about stis and hiv and aids is profoundly changed in rural-to-urban migrants ( , ) . the same result has been shown in a study among rural-to-urban migrants in ethiopia ). the rapid influx of migrants moving to cities makes it hard to get adequate information to all the different groups in the society. to educate the public is one of the many challenges for local governments and health officials. campaigns to improve the public knowledge are useful to fight the threat of infectious diseases. residents need to be aware of symptoms of infectious diseases to gain knowledge about when to seek health care and when it is safe to treat yourself. knowledge about food storage, waste management, vector control, and sanitary facilities are all aspects that can lower the burden of communicable diseases. these campaigns can sometimes be easier in the urban environment because of the density of the population. urbanization is an ongoing process in the world at the moment, but the pace of the process is not universal. the developed countries, which have traditionally been thought of as high-income countries, are already urbanized, and it is in the developing world that the rapid rise is taking place. infectious diseases still have a big impact on the global health, and urbanization is now altering the characteristics of these diseases. living conditions in cities are overall better in urban environments compared to rural settings; better housing, sanitation, ventilation, and social services all play an important role in this improvement. certain pathogens can, however, adapt to the different conditions and thus create a new challenge for both local governments and the global community. the capacity for surveillance, control programs, prevention, and public knowledge programs is far better in cities. it is here where the resources and political and financial power are gathered. but some countries do not have the resources and because these diseases can be of global concern, it is also the international community's responsibility to help and support with knowledge and resources. the rapid urbanization has also interfered in previously untouched ecosystems. these new settlements create new and closer encounters with wildlife, which can be a potential source of zoonotic diseases. these can be both previously known or new pathogens, which make the shift from their animal host to generate infections in humans. surveillance is of primary importance to monitor the burden of disease and will give both local authorities and the global community a chance for a quick response to public health threats. world urbanization prospects: revision highlights hidden cities: unmasking and overcoming health inequities in urban settings urbanization and human health urbanisation and infectious diseases in a globalised world the transition to a predominantly urban world and its underpinnings united nations human settlements programme (un-habitet) the top causes of death our cities, our health, our future Á acting on social determinants for health equity in urban settings facts: urban settings as a social determinant of health informal urban settlements and cholera risk in dar es salaam spatial and demographic patterns of cholera in ashanti region-ghana outbreak of cholera 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security in the st century dengue infections in travellers major west indies mrsa clones in human beings: do they travel with their hosts? global distribution of panton-valentine leucocidin Á positive methicillin-resistant staphylococcus aureus travel-associated faecal colonization with esbl-producing enterobacteriaceae: incidence and risk factors foreign travel is a major risk factor for colonization with escherichia coli producing ctx-m-type extended-spectrum beta-lactamases: a prospective study with swedish volunteers colonisation with escherichia coli resistant to ''critically important'' antibiotics: a high risk for international travellers global trends in emerging infectious diseases prediction and prevention of the next pandemic zoonosis ebola virus disease outbreak in west africa who statement on the meeting of the international health regulations emergency committee regarding the ebola outbreak in west africa ebola outbreaks who ebola response team. ebola virus disease in west africa Á the first months of the epidemic and forward projections ebola haemorrhagic fever fruit bats as reservoirs of ebola virus recent common ancestry of ebola zaire virus found in a bat reservoir world malaria report urbanization in sub-saharan africa and implication for malaria control urbanization, malaria transmission and disease burden in africa urbanization and the global malaria recession the effects of urbanization on global plasmodium vivax malaria transmission determinants of apparent rural-urban differentials in measles vaccination uptake in indonesia community participation and childhood immunization coverage: a comparative study of rural and urban communities of bayelsa state, south-south nigeria factors influencing childhood immunization in uganda reproductive and child health inequities in chandigarh union territory of india knowledge of causes, clinical features and diagnosis of common zoonoses among medical practitioners in tanzania nyströ m l. urban-rural and socioeconomic variations in the knowledge of stis and aids among bangladeshi adolescents talking about, knowing about hiv/aids in canada: a rural-urban comparison vulnerable but feeling safe: hiv risk among male rural-to-urban migrant workers in chengdu sexual behavior among employed male rural migrants in hiv-related sexual behaviors among migrants and non-migrants in rural ethiopia: role of rural to urban migration in hiv transmission i would like to thank the two anonymous reviewers for their insightful opinions. the author have not received any funding or benefits from industry or elsewhere to conduct this study. key: cord- - qg fn f authors: adiga, aniruddha; dubhashi, devdatt; lewis, bryan; marathe, madhav; venkatramanan, srinivasan; vullikanti, anil title: mathematical models for covid- pandemic: a comparative analysis date: - - journal: j indian inst sci doi: . /s - - - sha: doc_id: cord_uid: qg fn f covid- pandemic represents an unprecedented global health crisis in the last years. its economic, social and health impact continues to grow and is likely to end up as one of the worst global disasters since the pandemic and the world wars. mathematical models have played an important role in the ongoing crisis; they have been used to inform public policies and have been instrumental in many of the social distancing measures that were instituted worldwide. in this article, we review some of the important mathematical models used to support the ongoing planning and response efforts. these models differ in their use, their mathematical form and their scope. abstract | covid- pandemic represents an unprecedented global health crisis in the last years. its economic, social and health impact continues to grow and is likely to end up as one of the worst global disasters since the pandemic and the world wars. mathematical models have played an important role in the ongoing crisis; they have been used to inform public policies and have been instrumental in many of the social distancing measures that were instituted worldwide. in this article, we review some of the important mathematical models used to support the ongoing planning and response efforts. these models differ in their use, their mathematical form and their scope. models have been used by mathematical epidemiologists to support a broad range of policy questions. their use during covid- has been widespread. in general, the type and form of models used in epidemiology depend on the phase of the epidemic. before an epidemic, models are used for planning and identifying critical gaps and prepare plans to detect and respond in the event of a pandemic. at the start of a pandemic, policy makers are interested in asking questions such as: (i) where and how did the pandemic start, (ii) risk of its spread in the region, (iii) risk of importation in other regions of the world, (iv) basic understanding of the pathogen and its epidemiological characteristics. as the pandemic takes hold, researchers begin investigating: (i) various intervention and control strategies; usually pharmaceutical interventions do not work in the event of a pandemic and thus nonpharmaceutical interventions are most appropriate, (ii) forecasting the epidemic incidence rate, hospitalization rate and mortality rate, (iii) efficiently allocating scarce medical resources to treat the patients and (iv) understanding the change in individual and collective behavior and adherence to public policies. after the pandemic starts to slow down, modelers are interested in developing models related to recovery and long-term impacts caused by the pandemic. j. indian inst. sci. | vol xxx:x | xxx-xxx | journal.iisc.ernet.in as a result comparing models needs to be done with care. when comparing models: one needs to specify: (a) the purpose of the model, (b) the end user to whom the model is targeted, (c) the spatial and temporal resolution of the model, (d) and the underlying assumptions and limitations. we illustrate these issues by summarizing a few key methods for projection and forecasting of disease outcomes in the us and sweden. organization. the paper is organized as follows. in sect. we give preliminary definitions. section discusses us and uk centric models developed by researchers at the imperial college. section discusses metapopulation models focused on the us that were developed by our group at uva and the models developed by researchers at northeastern university. section describes models developed swedish researchers for studying the outbreak in sweden. in sect. we discuss methods developed for forecasting. section contains discussion, model limitations and concluding remarks. in a companion paper that appears in this special issue, we address certain complementary issues related to pandemic planning and response, including role of data and analytics. important note. the primary purpose of the paper is to highlight some of the salient computational models that are currently being used to support covid- pandemic response. these models, like all models, have their strengths and weaknesses-they have all faced challenges arising from the lack of timely data. our goal is not to pick winners and losers among these model; each model has been used by policy makers and continues to be used to advice various agencies. rather, our goal is to introduce to the reader a range of models that can be used in such situations. a simple model is no better or worse than a complicated model. the suitability of a specific model for a given question needs to be evaluated by the decision maker and the modeler. for epidemiology epidemiological models fall in two broad classes: statistical models that are largely data driven and mechanistic models that are based on underlying theoretical principles developed by scientists on how the disease spreads. data-driven models use statistical and machine learning methods to forecast outcomes, such as case counts, mortality and hospital demands. this is a very active area of research, and a broad class of techniques have been developed, including auto-regressive time series methods, bayesian techniques and deep learning , , , , , . mechanistic models of disease spread within a population , , , use mechanistic (also referred to as procedural or algorithmic) methods to describe the evolution of an epidemic through a population. the most common of these is the sir type models. hybrid models that combine mechanistic models with data driven machine learning approaches are also starting to become popular, e.g., . there are a number of models, which are referred to as sir class of models. these partition a population of n agents into three sets, each corresponding to a disease state, which is one of: susceptible (s), infective (i) and removed or recovered (r). the specific model then specifies how susceptible individuals become infectious, and then recover. in its simplest form (referred to as the basic compartmental model) , , , the population is assumed to be completely mixed. let s(t), i(t) and r(t) denote the number of people who are susceptible, infected and recovered states at time t, respectively. let s(t) = s(t)/n , then, the sir model can be described by the following system of ordinary differential equations where β is referred to as the transmission rate, and γ is the recovery rate. a key parameter in such a model is the "reproductive number", denoted by r = β/γ . at the start of an epidemic, much of the public health effort is focused on estimating r from observed infections . mass action compartmental models have been the workhorse for epidemiologists and have been widely used for over years. their strength comes from their simplicity, both analytically and from the standpoint of understanding the outcomes. software systems have been developed to solve such models and a number of associated tools have been built to support analysis using such models. although simple and powerful, mass action compartmental models do not capture the inherent heterogeneity of the underlying populations. significant amount of research has been conducted j. indian inst. sci. | vol xxx:x | xxx-xxx | journal.iisc.ernet.in to extend the model, usually in two broad ways. the first involves structured metapopulation models-these construct an abstraction of the mixing patterns in the population into m different sub-populations, e.g., age groups and small geographical regions, and attempt to capture the heterogeneity in mixing patterns across subpopulations. in other words, the model has states s j (t), i j (t), r j (t) for each subpopulation j. the evolution of a compartment x j (t) is determined by mixing within and across compartments. for instance, survey data on mixing across age groups have been used to construct age structured metapopulation models . more relevant for our paper are spatial metapopulation models, in which the subpopulations are connected through airline and commuter flow networks , , , , . main steps in constructing structured metapopulation models. this depends on the disease, population and the type of question being studied. the key steps in the development of such models for the spread of diseases over large populations include • constructing subpopulations and compartments: the entire population v is partitioned into subpopulations v j , within which the mixing is assumed to be complete. depending on the disease model, there are s j , e j , i j , r j compartments corresponding to the subpopulation v j (and more, depending on the disease)-these represent the number of individuals in v j in the corresponding state • mixing patterns among compartments: state transitions between compartments might depend on the states of individuals within the subpopulations associated with those compartments, as well as those who they come in contact with. for instance, the s j → e j transition rate might depend on i k for all the subpopulations who come in contact with individuals in v j . mobility and behavioral datasets are needed to model such interactions. such models are very useful at the early days of the outbreak, when the disease dynamics are driven to a large extent by mobility-these can be captured more easily within such models, and there is significant uncertainty in the disease model parameters. they can also model coarser interventions such as reduced mobility between spatial units and reduced mixing rates. however, these models become less useful to model the effect of detailed interventions (e.g., voluntary home isolation, school closures) on disease spread in and across communities. agent-based networked models (sometimes just called as agent-based models) extend metapopulation models further by explicitly capturing the interaction structure of the underlying populations. often such models are also resolved at the level of single individual entities (animals, humans, etc.). in this class of models, the epidemic dynamics can be modeled as a diffusion process on a specific undirected contact network g(v, e) on a population v-each edge e = (u, v) ∈ e implies that individuals (also referred to as nodes) u, v ∈ v come into contact main steps in setting up an agent-based model. while the specific steps depend on the disease, the population, and the type of question being studied, the general process involves the following steps: • construct a network representation g: the set v is the population in a region, and is available from different sources, such as census and landscan. however, the contact patterns are more difficult to model, as no real data are available on contacts between people at a large scale. instead, researchers have tried to model activities and mobility, from which contacts can be inferred, based on co-location. multiple approaches have been developed for this, including random mobility based on statistical models, and very detailed models based on activities in urban regions, which have been estimated through surveys, transportation data, and other sources, e.g., , , , , . • develop models of within-host disease progression: such models can be represented as finite state probabilistic timed transition models, which are designed in close coordination with biologists, epidemiologists, and parameterized using detailed incidence data (see for discussion and additional pointers). • develop high-performance computer (hpc) simulations to study epidemic dynamics in such models, e.g., , , , . typical public health analyses involve large experimental designs, and the models are stochastic; this necessitates the use of such hpc simulations on large computing clusters. • incorporate interventions and behavioral changes: interventions include closure of schools and workplaces , and vaccinations ; whereas, behavioral changes include individual level social distancing, changes in mobility, and use of protective measures. such a network model captures the interplay between the three components of computational epidemiology: (i) individual behaviors of agents, (ii) unstructured, heterogeneous multi-scale networks, and (iii) the dynamical processes on these networks. it is based on the hypothesis that a better understanding of the characteristics of the underlying network and individual behavioral adaptation can give better insights into contagion dynamics and response strategies. although computationally expensive and data intensive, network-based epidemiology alters the types of questions that can be posed, providing qualitatively different insights into disease dynamics and public health policies. it also allows policy makers to formulate and investigate potentially novel and contextspecific interventions. like projection approaches, models for epidemic forecasting can be broadly classified into two broad groups: (i) statistical and machine learning-based data-driven models, (ii) causal or mechanistic models-see , , , , , , and the references therein for the current state of the art in this rapidly evolving field. statistical methods employ statistical and time series-based methodologies to learn patterns in historical epidemic data and leverage those patterns for forecasting. of course, the simplest yet useful class is called method of analogs. one simply compares the current epidemic with one of the earlier outbreaks and then uses the best match to forecast the current epidemic. popular statistical methods for forecasting influenzalike illnesses (that includes covid- ) include, e.g., generalized linear models (glm), autoregressive integrated moving average (arima), and generalized autoregressive moving average (garma) , , . statistical methods are fast, but they crucially depend on the availability of training data. furthermore, since they are purely data driven, they do not capture the underlying causal mechanisms. as a result, epidemic dynamics affected by behavioral adaptations are usually hard to capture. artificial neural networks (ann) have gained increased prominence in epidemic forecasting due to their self-learning ability without prior knowledge (see , , and the references therein). such models have used a wide variety of data as surrogates for producing forecasts. this includes: (i) social media data, (ii) weather data, (iii) incidence curves and (iv) demographic data. causal models can be used for epidemic forecasting in a natural manner , , , , , . these models calibrate the internal model parameters using the disease incidence data seen until a given day and then execute the model forward in time to produce the future time series. compartmental as well as agentbased models can be used to produce such forecasts. the choice of the models depends on the specific question at hand and the computational and data resource constraints. one of the key ideas in forecasting is to develop ensemble models-models that combine forecasts from multiple models , , , . the idea which originated in the domain of weather forecasting has found methodological advances in the machine learning literature. ensemble models typically show better performance than the individual models. modeling group (uk model) background. the modeling group led by neil ferguson was to our knowledge the first model to study the impact of covid- across two large countries: us and uk, see . the basic model was first developed in -it was used to inform policy pertaining to h n pandemic and was one of the three models used to inform the federal pandemic influenza plan and led to the now well-accepted targeted layered containment (tlc) strategy. it was adapted to covid- as discussed below. the model was widely discussed and covered in the scientific as well as popular press . we will refer to this as the ic model. model structure. the basic model structure consists of developing a set of households based on census information for a given country. the structure of the model is largely borrowed from their earlier work, see , . landscan data were used to spatially distribute the population. individual members of the household interact with other members of the household. the data to produce these households are obtained using census information for these countries. census data are used to assign age and household sizes. details on the resolution of census data and the dates were not clear. schools, workplaces and random meeting points are then added. the school data for us were obtained from the national centre of educational statistics, while for uk schools were assigned randomly based on population density. data on average class sizes and staff-student ratios were used to generate a synthetic population of schools distributed proportional to local population density. data on the distribution of workplace size were used to generate workplaces with commuting distance data used to locate workplaces appropriately across the population. individuals are assigned to each of these locations at the start of the simulation. the gravity-style kernel is used to decide how far a person can go in terms of attending work, school or community interaction place. the number of contacts between individuals at school, work and community meeting points are calibrated to produce a given attack rate. each individual has an associated disease transmission model. the disease transmission model parameters are based on the data collected when the pandemic was evolving in wuhan; see page of . finally, the model also has rich set of interventions. these include: (i) case isolation, (ii) voluntary home quarantine, (iii) social distancing of those over years, (iv) social distancing of the entire population, (v) closure of schools and universities; see page . the code was recently released and is being analyzed. this is important as the interpretation of these interventions can have substantial impact on the outcome. model predictions. the imperial college (ic model) model was one of the first models to evaluate the covid- pandemic using detailed agentbased model. the predictions made by the model were quite dire. the results show that to be able to reduce r to close to or below, a combination of case isolation, social distancing of the entire population and either household quarantine or school and university closure is required. the model had tremendous impact-uk and us both decide to start considering complete lock downs-a policy that was practically impossible to even talk about earlier in the western world. the paper came out around the same time that wuhan epidemic was raging and the epidemic in italy had taken a turn for the worse. this made the model results even more critical. strengths and limitations. ic model was one of the first models by a reputed group to report the potential impact of covid- with and without interventions. the model was far more detailed than other models that were published until then. the authors also took great care parameterizing the model with the best disease transmission data that was available until then. the model also considered a very rich set of interventions and was one of the first to analyze pulsing intervention. on the flip side, the representation of the underlying social contact network was relatively simple. second, often the details of how interventions were represented were not clear. since the publication of their article, the modelers have made their code open and the research community has witnessed an intense debate on the pros and cons of various modeling assumptions and the resulting software system, see . we believe that despite certain valid criticisms, overall, the results represented a significant advance in terms of the when the results were put out and the level of details incorporated in the models. northeastern and uva models (us models) background. this approach is an alternative to detailed agent-based models, and has been used in modeling the spread of multiple diseases, including influenza , , ebola and zika . it has been adapted for studying the importation risk of covid- across the world . structured metapopulation models construct a simple abstraction of the mixing patterns in the population, in which the entire region under study is decomposed into fully connected geographical regions, representing subpopulations, which are connected through airline and commuter flow networks. thus, they lack the rich detail of agent-based models, but have fewer parameters, and are, therefore, easy to set up and scale to large regions. model structure. here, we summarize gleam (northeastern model) and patchsim (uva model). gleam uses two classes of datasets-population estimates and mobility. population data are used from the "gridded population of the world" , which gives an estimated population value at a × minutes of arc (referred to as a "cell") over the entire planet. two different kinds of mobility processes are considered-airline travel and commuter flow. the former captures long-distance travel; whereas, the latter captures localized mobility. airline data are obtained from the international air transport association (iata) , and the official airline guide (oag) . there are about airports world wide; these are aggregated at the level of urban regions served by multiple airport (e.g., as in london). a voronoi tessellation is constructed with the resulting airport locations as centers, and the population cells are assigned to these cells, with a mile cutoff from the center. the commuter flows connect cells at a much smaller spatial scale. we represent this mobility pattern as a directed graph on the cells, and refer to it as the mobility network. in the basic seir model, the subpopulation in each cell j is partitioned into compartments s j , e j , i j and r j , corresponding to the disease states. for each cell j, we define the force of infection j as the rate at which a susceptible individual in the subpopulation in cell j becomes infected-this is determined by the interactions the person has with infectious individuals in cell j or any cell j ′ connected in the mobility network. an individual in the susceptible compartment s j becomes infected with probability j t and enters the compartment e j , in a time interval t . from this compartment, the individual moves to the i j and then the r j compartments, with appropriate probabilities, corresponding to the disease model parameters. the patchsim model has a similar structure, except that it uses administrative boundaries (e.g., counties), instead of a voronoi tesselation, which are connected using a mobility network. the mobility network is derived by combining commuter and airline networks, to model time spent per day by individuals of region (patch) i in region (patch) j. since it explicitly captures the level of connectivity through a commuter-like mixing, it is capable of incorporating week-toweek and month-to-month variations in mobility and connectivity. in addition to its capability to run in deterministic or stochastic mode, the open source implementation allows fine-grained control of disease parameters across space and time. although the model has a more generic force of infection mode of operation (where patches can be more general than spatial regions), we will mainly summarize the results from the mobility model, which was used for covid- response. what did the models suggest? gleam model is being used in a number of covid- -related studies and analysis. in , the northeastern university team used the model to understand the spread of covid- within china and relative risk of importation of the disease internationally. their analysis suggested that the spread of covid- out of wuhan into other parts of mainland china was not contained well due to the delays induced by detection and official reporting. it is hard to interpret the results. the paper suggested that international importation could be contained substantially by strong travel ban. while it might have delayed the onset of cases, the subsequent spread across the world suggest that we were not able to arrest the spread effectively. the model is also used to provide weekly projections (see https ://covid .gleam proje ct.org/); this site does not appear to be maintained for the most current forecasts (likely because the team is participating in the cdc forecasting group). the patchsim model is being used to support federal agencies as well as the state of virginia. due to our past experience, we have refrained from providing longer term forecasts, instead of focusing on short-term projections. the model is used within a forecasting via projection selection approach, where a set of counterfactual scenarios are generated based on on-the-ground response efforts and surveillance data, and the best fits are selected based on historical performance. while allowing for future scenarios to be described, they also help to provide a reasonable narrative of past trajectories, and retrospective comparisons are used for metrics such as 'cases averted by doing x' . these projections are revised weekly based on stakeholder feedback and surveillance update. further discussion of how the model is used by the virginia department of health each week can be found at https ://www.vdh.virgi nia.gov/coron aviru s/covid - -data-insig hts/#model . strength and limitations. structured metapopulation models provide a good tradeoff between the realism/compute of detailed agentbased models and simplicity/speed of mass action compartmental models and need far fewer inputs for modeling, and scalability. this is especially true in the early days of the outbreak, when the disease dynamics are driven to a large extent by mobility, which can be captured more easily within such models, and there is significant uncertainty in the disease model parameters. however, once the outbreak has spread, it is harder to model detailed interventions (e.g., social distancing), which are much more localized. further, these are hard to model using a single parameter. both gleam and patchsim models also faced their share of challenges in projecting case counts due to rapidly evolving pandemic, inadequate testing, a lack of understanding of the number of asymptomatic cases and assessing the compliance levels of the population at large. researchers (swedish models) sweden was an outlier amongst countries in that it decided to implement public health interventions without a lockdown. schools and universities were not closed, and restaurants and bars remained open. swedish citizens implemented "work from home" policies where possible. moderate social distancing based on individual responsibility and without police enforcement was employed but emphasis was attempted to be placed on shielding the + age group. background. statistician tom britton developed a very simple model with a focus on predicting the number of infected over time in stockholm. model structure. britton used a very simple sir general epidemic model. it is used to make a coarse grain prediction of the behavior of the outbreak based on knowing the basic reproduction number r and the doubling time d in the initial phase of the epidemic. calibration to calendar time was done using the observed number of case fatalities, together with estimates of the time between infection to death, and the infection fatality risk. predictions were made assuming no change of behavior, as well as for the situation where preventive measures are put in place at one specific time-point. model predictions. one of the controversial predictions from this model was that the number of infections in the stockholm area would quickly rise towards attaining herd immunity within a short period. however, mass testing carried out in stockholm during june indicated a far smaller percentage of infections. strength and limitations. britton's model was intended as a quick and simple method to estimate and predict an on-going epidemic outbreak both with and without preventive measures put in place. it was intended as a complement to more realistic and detailed modeling. the estimation-prediction methodology is much simpler and straight-forward to implement for this simple model. it is more transparent to see how the few model assumptions affect the results, and it is easy to vary the few parameters to see their effect on predictions so that one could see which parameter uncertainties have biggest impact on predictions, and which parameter uncertainties are less influential. model background. the public health authority (fhm) of sweden produced a model to study the spread of covid- in four regions in sweden: dalarna, skåne, stockholm, and västra götaland. . model structure. it is a standard compartmentalized seir model and within each compartment, it is homogeneous; so, individuals are assumed to have the same characteristics and act in the same way. data used in the fitting of the model include point prevalences found by pcrtesting in stockholm at two different time points. model predictions. the model estimated the number of infected individuals at different time points and the date with the largest number of infectious individuals. it predicted that by july , . % ( . - . %) of the population in dalarna will have been infected, % ( . - . %) of the population in skåne will have been infected, % ( . - . %) of the population in stockholm will have been infected, and % ( . - . %) of the population in västra götaland will have been infected. it was hard to test these predictions because of the great uncertainty in immune response to sars-cov- -prevalence of antibodies was surprisingly low but recent studies show that mild cases never seem to develop antibodies against sars-cov- , but only t-cellmediated immunity . the model also investigated the effect of increased contacts during the summer that stabilizes in autumn. it found that if the contacts in stockholm and dalarna increase by less than % in comparison to the contact rate in the beginning of june, the second wave will not exceed the observed first wave. strength and limitations. the simplicity of the model is a strength in ease of calibration and understanding but it is also a major limitation in view of the well-known characteristics of covid- : since it is primarily transmitted through droplet infection, the social contact structure in the population is of primary importance for the dynamics of infection. the compartmental model used in this analysis does not account for variation in contacts, where few individuals may have many contacts, while the majority have fewer. the model is also not age stratified, but covid- strikingly affects different age groups differently; e.g., young people seem to get milder infections. in this model, each infected individual has the same infectivity and the same risk of becoming a reported case, regardless of age. different age groups normally have varied degrees of contacts and have changed their behavior differently during the covid- pandemic. this is not captured in the model. rocklöv developed a model to estimate the impact of covid- on the swedish population at the municipality level, considering demography and human mobility under various scenarios of mitigation and suppression. they attempted to estimate the time course of infections, health care needs, and the mortality in relation to the swedish icu capacity, as well as the costs of care, and compared alternative policies and counterfactual scenarios. model structure. used a seir compartmentalized model with age structured compartments ( - , - , +) susceptibles, infected, in-patient care, icu and recovered populations based on swedish population data at the municipal level. it also incorporated inter-municipality travel using a radiation model. parameters were calibrated based on a combination of values available from international literature and fitting to available outbreak data. the effect of a number of different intervention strategies was considered ranging from no intervention to modest social distancing and finally to imposed isolation of various groups. model predictions. the model predicted an estimated death toll of around , for the strategies based only on social distancing and between and for policies imposing stricter isolation. it predicted icu cases of up to , without much intervention and up to with modest social distancing, way above the available capacity of about icu beds. strength and limitations. the model showed a good fit against the reported covid- -related deaths in sweden up to th of april, , however, the predictions of the total deaths and icu demand turned out to be way off the mark. background. finally, , used an individualbased model parameterized on swedish demographics to assess the anticipated spread of covid- . model structure. employed the individual agent-based model based on work by ferguson et al. . individuals are randomly assigned an age based on swedish demographic data and they are also assigned a household. household size is normally distributed around the average household size in sweden in , . people per household. households were placed on a lattice using high-resolution population data from landscan and census dara from the statstics sweden and each household is additionally allocated to a city based on the closest city center by distance and to a county based on city designation. each individual is placed in a school or workplace at a rate similar to the current participation in sweden. transmission between individuals occurs through contact at each individual's workplace or school, within their household, and in their communities. infectiousness is, thus, a property dependent on contacts from household members, school/workplace members and community members with a probability based on household distances. transmissibility was calibrated against data for the period march- april to reproduce either the doubling time reported using pan-european data or the growth in reported swedish deaths for that period. various types of interventions were studied including the policy implemented in sweden by the public health authorities as well as more aggressive interventions approaching full lockdown. model predictions. their prediction was that "under conservative epidemiological parameter estimates, the current swedish public-health strategy will result in a peak intensive-care load in may that exceeds pre-pandemic capacity by over -fold, with a median mortality of , ( % ci , to , )". strength and limitations. this model was based on adapting the well-known imperial model discussed in sect. to sweden and considered a wide range of intervention strategies. unfortunately the predictions of the model were woefully off the mark on both counts: the deaths by june are under and at the peak the icu infrastructure had at least % unutilized capacity. forecasting is of particular interest to policy makers as they attempt to provide actual counts. since the surveillance systems have relatively stabilized in recent weeks, the development of forecasting models has gained traction and several models are available in the literature. in the us, the centers for disease control and prevention (cdc) has provided a platform for modelers to share their forecasts which are analyzed and combined in a suitable manner to produce ensemble multi-week forecasts for cumulative/incident deaths, hospitalizations and more recently cases at the national, state, and county level. probabilistic forecasts are provided by teams as of july , (there were models as of june , ) and the cdc with the help of has developed uniform ensemble model for multi-step forecasts . model it has been observed previously for other infectious diseases that an ensemble of forecasts from multiple models perform better than any individual contributing model . in the context of covid- case count modeling and forecasting, a multitude of models have been developed based on different assumptions that capture specific aspects of the disease dynamics (reproduction number evolution, contact network construction, etc.). the models employed in the cdc forecast hub can be broadly classified into three categories, data-driven, hybrid models, and mechanistic models with some of the models being open source. data-driven models. they do not model the disease dynamics but attempt to find patterns in the available data and combine them appropriately to make short-term forecasts. in such data-driven models, it is hard to incorporate interventions directly; hence, the machine is presented with a variety of exogenous data sources such as mobility data, hospital records, etc. with the hope that its effects are captured implicitly. early iterations of institute of health metrics and evaluation (ihme) model for death forecasting at state level employed a statistical model that fits a time-varying gaussian error function to the cumulative death counts and is parameterized to control for maximum death rate, maximum death rate epoch, and growth parameter (with many parameters learnt using data from outbreak in china). the ihme models are undergoing revisions (moving towards the hybrid models) and updated implementable versions are available at . the university of texas at austin covid- modeling consortium model uses a very similar statistical model as but employs real-time mobility data as additional predictors and also differ in the fitting process. the carnegie mellon delphi group employs the well known auto-regressive (ar) model that employs lagged version of the case counts and deaths as predictors and determines a sparse set that best describes the observations from it by using j. indian inst. sci. | vol xxx:x | xxx-xxx | journal.iisc.ernet.in lasso regression . is a deep learning model which has been developed along the lines of and attempts to learn the dependence between death rate and other available syndromic, demographic, mobility and clinical data. hybrid models. these methods typically employ statistical techniques to model disease parameters which are then used in epidemiological models to forecast cases. most statistical models , are evolving to become hybrid models. a model that gained significant interest is the youyang gu (yyg) model and uses a machine learning layer over an seir model to learn the set of parameters (mortality rate, initial r , postlockdown r) specific to a region that best fits the region's observed data. the authors (yyg) share the optimal parameters, the seir model and the evaluation scripts with general public for experimentation . los alamos national lab (lanl) model uses a statistical model to determine how the number of covid- infections changes over time. the second process maps the number of infections to the reported data. the number of deaths is a fraction of the number of new cases obtained and is computed using the observed mortality data. mechanistic models. gleam and jhu models are county-level stochastic seir model dynamics. the jhu model incorporates the effectiveness of state-wide intervention policies on social distancing through the r parameter. more recently, model outputs from uva's patchsim model were included as part of a multi-model ensemble (including autoregressive and lstm components) to forecast weekly confirmed cases. types we end the discussion of the models above by qualitatively comparing model types. as discussed in the preliminaries, at one end of the spectrum are models that are largely data driven: these models range from simple statistical models (various forms of regression models) to the more complicated deep learning models. the difference in such model lies in the amount of training data needed, the computational resources needed and how complicated the mathematical function one is trying to fit to the observed data. these models are strictly data driven and, hence, unable to capture the constant behavioral adaptation at an individual and collective level. on the other end of the spectrum seir, meta-population and agent-based network models are based on the underlying procedural representation of the dynamics-in theory, they are able to represent behavioral adaptation endogenously. but both class of models face immense challenges due to the availability of data as discussed below. ( ) agent-based and seir models were used in all the three countries in the early part of the outbreak and continue to be used for counter-factual analysis. the primary reason is the lack of surveillance and disease specific data and hence, purely data-driven models were not easy to use. seir models lacked heterogeneity but were simple to program and analyze. agent-based models were more computationally intensive, required a fair bit of data to instantiate the model but captured the heterogeneity of the underlying countries. by now it has become clear that use of such models for long term forecasting is challenging and likely to lead to mis-leading results. the fundamental reason is adaptive human behavior and lack of data about it. ( ) forecasting, on the other hand, has seen use of data-driven methods as well as causal methods. short-term forecasts have been generally reasonable. given the intense interest in the pandemic, a lot of data are also becoming available for researchers to use. this helps in validating some of the models further. even so, realtime data on behavioral adaptation and compliance remain very hard to get and is one of the central modeling challenges. were some of the models wrong? in a recent opinion piece, professor vikram patel of the harvard school of public health makes a stinging criticism of modeling: crowning these scientific disciplines is the field of modeling, for it was its estimates of mountains of dead bodies which fuelled the panic and led to the unprecedented restrictions on public life around the world. none of these early models, however, explicitly acknowledged the huge assumptions that were made, a similar article in ny times recounted the mistakes in covid- response in europe ; also see . our point of view. it is indeed important to ensure that assumptions underlying mathematical models be made transparent and explicit. but we respectfully disagree with professor patel's statement: most of the good models tried to be very explicit about their assumptions. the mountains of deaths that are being referred to are explicitly calculated when no interventions are put in place and are often used as a worst case scenario. now, one might argue that the authors be explicit and state that this worst case scenario will never occur in practice. forecasting dynamics in social systems is inherently challenging: individual behavior, predictions and epidemic dynamics co-evolve; this coevolution immediately implies that a dire prediction can lead to extreme change in individual and collective behavior leading to reduction in the incidence numbers. would one say forecasts were wrong in such a case or they were influential in ensuring the worst case never happens? none of this implies that one should not explicitly state the assumption underlying their model. of course our experience is that policy makers, news reporters and common public are looking exactly for such a forecastwe have been constantly asked "when will peak occur" or "how many people are likely to die". a few possible ways to overcome this tension between the unsatiable appetite for forecasts and the inherent challenges that lie in doing this accurately, include: • we believe that, in general, it might not be prudent to provide long term forecasts for such systems. • state the assumptions underlying the models as clearly as possible. modelers need to be much more disciplined about this. they also need to ensure that the models are transparent and can be reviewed broadly (and expeditiously). • accept that the forecasts are provisional and that they will be revised as new data comes in, society adapts, the virus adapts and we understand the biological impact of the pandemic. • improve surveillance systems that would produce data that the models can use more effectively. even with data, it is very hard to estimate the prevalence of covid- in society. communicating scientific findings and risks is an important topical area in this context, see , , , . use of models for evidence-based policy making. in a new book, , radical uncertainty, economists john kay and mervyn king (formerly governor of the bank of england) urge caution when using complex models. they argue that models should be valued for the insights they provide but not relied upon to provide accurate forecasts. the so-called "evidence-based policy" comes in for criticism where it relies on models but also supplies a false sense of certainty where none exists, or seeks out the evidence that is desired ex ante-or "cover"--to justify a policy decision. "evidence-based policy has become policy-based evidence". our point of view. the authors make a good point here. but again, everyone, from public to citizens and reporters clamor for a forecast. we argue that this can be addressed in two ways:(i) viewing the problem from the lens of control theory so that we forecast only to control the deviation from the path we want to follow and (ii) not insisting on exact numbers but general trends. as kay and king opine, the value of models, especially in the face of radical uncertainty, is more in exploring alternative scenarios resulting from different policies: a model is useful only if the person using it understands that it does not represent the "the world as it really is" but is a tool for exploring ways in which a decision might or might not go wrong. in his new book the rules of contagion, adam kucharski draws on lessons from the past. in and , during the zika outbreak, researchers planned large-scale clinical studies and vaccine trials. but these were discontinued as soon as the infection ebbed. this is a common frustration in outbreak research; by the time, the infections end, fundamental questions about the contagion can remain unanswered. that is why building long-term research capacity is essential. our point of view. the author makes an important point. we hope that today, after witnessing the devastating impacts of the pandemic on the economy and society, the correct lessons will be learnt: sustained investments need to be made in the field to be ready for the impact of the next pandemic. the paper discusses a few important computational models developed by researchers in the us, uk and sweden for covid- pandemic planning and response. the models have been used by policy makers and public health officials in their respective countries to assess the evolution of the pandemic, design and analyze control measures and study various what-if scenarios. as noted, all models faced challenges due to availability of data, rapidly evolving pandemic and unprecedented control measures put in place. despite these challenges, we believe that mathematical models can provide useful and timely information to the policy makers. on on hand the modelers need to be transparent in the description of their models, clearly state the limitations and carry out detailed sensitivity and uncertainty quantification. having these models reviewed independently is certainly very helpful. on the other hand, policy makers should be aware of the fact that using mathematical models for pandemic planning, forecast response rely on a number of assumptions and lack data to over these assumptions. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. epideep: exploiting embeddings for epidemic forecasting real-time epidemic forecasting: challenges and opportunities real-time forecasting of infectious disease dynamics with a stochastic semi-mechanistic model forecasting 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firstwave covid- deaths across the us using social-distancing measures derived from mobile phones policy implications of models of the spread of coronavirus: perspectives and opportunities for economists evaluating science communication mathematical models to guide pandemic response infodemic and risk communication in the era of cov- radical uncertainty: decision-making beyond the numbers the rules of contagion: why things spread-and why they stop. basic books the authors would like to thank members of the biocomplexity covid- response team and network systems science and advanced computing (nssac) division for their thoughtful comments and suggestions related to epidemic modeling and response support. we thank members of the biocomplexity institute and initiative, university of virginia for useful discussion and suggestions. this work was partially sup- research associate at the nssac division of the biocomplexity institute and initiative. he completed his phd from the department of electrical engineering, indian institute of science (iisc), bangalore, india and has held the position of postdoctoral fellow at iisc and north carolina state university, raleigh, usa. his research areas include signal processing, machine learning, data mining, forecasting, big data analysis etc. at nssac, his primary focus has been the analysis and development of forecasting systems for epidemiological signals such as influenza-like illness and covid- using auxiliary data sources. bryan lewis is a research associate professor in the network systems science and advanced computing division. his research has focused on understanding the transmission dynamics of infectious diseases within specific populations through both analysis and simulation. lewis is a computational epidemiologist with more than years of experience in crafting, analyzing, and interpreting the results of models in the context of real public health problems. as a computational epidemiologist, for more than a decade, lewis has been heavily involved in a series of projects forecasting the spread of infectious disease as well as evaluating the response to them in support of the federal government. these projects have tackled diseases from ebola to pandemic influenza and melioidosis to cholera. professor in biocomplexity, the division director of the networks, simulation science and advanced computing (nssac) division at the biocomplexity institute and initiative, and a professor in the department of computer science at the university of virginia (uva). his research interests are in network science, computational epidemiology, ai, foundations of computing, socially coupled system science and high-performance computing. before joining uva, he held positions at virginia tech and the los alamos national laboratory. he is a fellow of the ieee, acm, siam and aaas. scientist at the biocomplexity institute & initiative, university of virginia and his research focuses on developing, analyzing and optimizing computational models in the field of network epidemiology. he received his phd from the department of electrical and communication engineering, indian institute of science (iisc), and did his postdoctoral research at virginia tech. his areas of interest include network science, stochastic modeling and big data analytics. he has used in-silico models of society to study the spread of infectious diseases and invasive species. recent research includes modeling and forecasting emerging infectious disease outbreaks (e.g., ebola, covid- ), impact of human mobility on disease spread and resource allocation problems in the context of key: cord- - t mu s authors: wynne, keona jeane; petrova, mila; coghlan, rachel title: dying individuals and suffering populations: applying a population-level bioethics lens to palliative care in humanitarian contexts: before, during and after the covid- pandemic date: - - journal: j med ethics doi: . /medethics- - sha: doc_id: cord_uid: t mu s background: humanitarian crises and emergencies, events often marked by high mortality, have until recently excluded palliative care—a specialty focusing on supporting people with serious or terminal illness or those nearing death. in the covid- pandemic, palliative care has received unprecedented levels of societal attention. unfortunately, this has not been enough to prevent patients dying alone, relatives not being able to say goodbye and palliative care being used instead of intensive care due to resource limitations. yet global guidance was available. in , the who released a guide on ‘integrating palliative care and symptom relief into the response to humanitarian emergencies and crises’—the first guidance on the topic by an international body. aims: this paper argues that while a landmark document, the who guide took a narrowly clinical bioethics perspective and missed crucial moral dilemmas. we argue for adding a population-level bioethics lens, which draws forth complex moral dilemmas arising from the fact that groups having differential innate and acquired resources in the context of social and historical determinants of health. we discuss dilemmas concerning: limitations of material and human resources; patient prioritisation; euthanasia; and legacy inequalities, discrimination and power imbalances. implications: in parts of the world where opportunity for preparation still exists, and as countries emerge from covid- , planners must consider care for the dying. immediate steps to support better resolutions to ethical dilemmas of the provision of palliative care in humanitarian and emergency contexts will require honest debate; concerted research effort; and international, national and local ethical guidance. abstract background humanitarian crises and emergencies, events often marked by high mortality, have until recently excluded palliative care-a specialty focusing on supporting people with serious or terminal illness or those nearing death. in the covid- pandemic, palliative care has received unprecedented levels of societal attention. unfortunately, this has not been enough to prevent patients dying alone, relatives not being able to say goodbye and palliative care being used instead of intensive care due to resource limitations. yet global guidance was available. in , the who released a guide on 'integrating palliative care and symptom relief into the response to humanitarian emergencies and crises'-the first guidance on the topic by an international body. aims this paper argues that while a landmark document, the who guide took a narrowly clinical bioethics perspective and missed crucial moral dilemmas. we argue for adding a population-level bioethics lens, which draws forth complex moral dilemmas arising from the fact that groups having differential innate and acquired resources in the context of social and historical determinants of health. we discuss dilemmas concerning: limitations of material and human resources; patient prioritisation; euthanasia; and legacy inequalities, discrimination and power imbalances. implications in parts of the world where opportunity for preparation still exists, and as countries emerge from covid- , planners must consider care for the dying. immediate steps to support better resolutions to ethical dilemmas of the provision of palliative care in humanitarian and emergency contexts will require honest debate; concerted research effort; and international, national and local ethical guidance. background humanitarian crises and emergencies, events that are often marked by high mortality, have until recently excluded palliative care-a specialty focusing precisely on supporting people with serious or terminal illness or those nearing the end of life. awareness of this paradox has recently been rising and a growing body of literature has been calling for the inclusion of palliative care into humanitarian and emergency responses. [ ] [ ] [ ] [ ] [ ] [ ] [ ] a seismic shift of attention is also happening now across all parts of the world-not only in pre-existing humanitarian crises-in the context of the covid- pandemic. as of may , the international association for hospice and palliative care (iahpc) lists over 'resources relevant to palliative care and covid- '. often unknowingly, this growing attention to palliative care revives the history of modern (western) humanitarianism in emergency and crisis response. in one of the humanitarian sector's formative documents, henry dunant depicts the harrowing suffering he encountered in stumbling across the battle of solferino in . dunant suggested that compassionate care shown in accompanying and soothing the dying should be the foundation of humanitarian action. in the + years since dunant's experience, the capacity of both modern medicine and the broader humanitarian response to save lives has increased dramatically and continues to do so. saving lives has become the paramount goal for both. since the middle of the th century however, medicine has also evolved a branch specifically aimed at alleviating the suffering of those who cannot be cured and/or are dying. this is palliative care, which aims to prevent and relieve physical, emotional, social or spiritual suffering associated with any chronic or life-threatening illness and to promote dignity in suffering, death and dying. humanitarianism and palliative care share both fundamental goals around easing suffering and upholding dignity, and a moral root in the recognition of our common suffering, fragility and humanity. powell et al suggest four types of humanitarian scenarios for which the provision of palliative care is especially relevant: ( ) protracted conflicts where people endure life-limiting illnesses; ( ) acute mass-casualty events where individuals are triaged based on likelihood to survive; ( ) communicable disease outbreaks with limited therapeutic intervention options; and ( ) within refugee and displaced persons camps. the ubiquity of such scenarios and benefits of palliative care to these populations demand the inclusion of palliative care within the humanitarian response. at the time of editing this article, we are in the midst of the covid- pandemic, an infectious disease caused by a newly discovered virus in the coronavirus family, for which there is currently no vaccine and no specific antiviral medicines. as of today ( may ) , the data from the who are for confirmed cases; confirmed deaths; and countries, areas or territories with cases. from a palliative care perspective, this means that over , covid- deaths, each of the critical care cases, and many more unrecorded patients who are dying or have died with or without covid- in the time of the pandemic, should have been considered for and typically offered palliative and end-of-life care. this is unlikely to be happening on such a large scale. yet health systems across the world have had, for about a year and a half, clear guidance on the crucial importance of palliative care in humanitarian emergencies and the need to include palliative care in emergency preparedness. in september , who released a guide on 'integrating palliative care and symptom relief into the response to humanitarian emergencies and crises' -the very first guidance document on the topic by a pre-eminent international body. the publication of the guide was a landmark moment for the field of palliative care in humanitarian settings. if governments, healthcare providers and humanitarian organisations have been swift to begin integrating its philosophy and practical recommendations in their planning, their efforts are likely to be rewarded in the current pandemic context. yet a little over a year is almost as brief as the blink of an eye for the system transformation required, without the dramatic force of events as the ones we see unfolding. we are not aware of evidence of the guide's uptake in the aftermath of its publication, including in responses to covid- . indeed, any reference to the guide or to palliative care are omitted from recent covid- emergency and humanitarian response plans (eg, who's 'covid- operational guidance for maintaining essential health services during an outbreak' and the un office for the coordination of humanitarian affairs' 'global humanitarian response plan covid- '). we hope the guide's application has been far more widespread than the lack of references and formal evaluations may suggest, but this remains, for now, an open research question. and while no first major document of its kind could have withstood the challenge of covid- , we still need to scruitinise the guide for shortcomings and opportunities to improve on them and not only criticise the (likely) limitations of its uptake. some of the guide's most important shortcomings concern, from our perspective, issues of ethics. this is the focus of our paper. we argue that the who guide has employed, predominately, an ethical lens shaped by clinical bioethics, with its concern for the rights and well-being of individual patients and their interactions with healthcare providers. we propose that a future version of the guide will be dramatically enhanced in its ethical discussion by the incorporation of a population-level bioethics lens, among others. in a manner that is both contrasting and complementary to clinical bioethics, population-level bioethics focuses on the obligations of society to its members as individuals and groups. one of the fundamental contentions of population-level bioethics is that different segments or subgroups within a society will require varying 'right actions' due to differential access, availability and opportunity to use resources. we suggest that palliative care has limited chances of becoming a recognised and integrated component of the humanitarian and emergency response unless we explore such obligations and the dilemmas associated with them. we are also forced to explore those issues now. many healthcare professionals, emergency services staff and humanitarian workers, as well as organisational leaders and policy-makers are shaken by powerlessness, guilt and fear from witnessing covid- deaths which could have been avoided with better preparation; from being aware of the suffering and loneliness of those who are dying, while all available staff are needed to fight for the lives of those with higher chances of survival; or, with a growing likelihood, from contemplating decisions about withholding or withdrawing critical treatment because of severe resource limitations. they are grappling with what slim calls 'hellish choices'. doctors and ethicists across countries such as italy, the usa, the uk and australia have, expectedly, quickly seen the need to develop ethical guidance and decision-making frameworks to guide tough resource allocation and triage choices. [ ] [ ] [ ] [ ] [ ] [ ] we are living and witnessing harrowing experiences and tradeoffs relevant to palliative care on a daily basis, yet these dilemmas did not receive a mention in the who guide. overall, the guide lacked a basic recognition of their existence, acuity and, potentially, ultimate irresolvability. and while we could not have imagined them easily on a global scale, they were painfully familiar to anyone who has worked in a humanitarian crisis or emergency. it is as if the issues we wanted to avoid by not thinking of the worst came back to haunt us. our analysis begins with a summary of the ethical discussion in the who guide. we then present briefly the distinct visual fields revealed by a clinical bioethics lens and a population-level bioethics lens. we describe in greater detail the population-level bioethics perspective, as it is relatively unfamiliar in the broader ethics community and often misperceived as a form of utilitarianism in a healthcare context. (to some degree, this may be an issue of nomenclature-the name of 'population-level bioethics' does not do justice to the key considerations underpinning the approach.) we argue that the pattern of representation of ethical issues in the who guide is consistent with over-reliance on a clinical bioethics lens. the core of the paper then outlines four sets of ethical concerns and dilemmas around the provision of palliative care in humanitarian emergencies and crises which become more visible once we expand our lens to think about who comprises the entirety of a population. these sets of concerns and dilemmas arise in relation to ( ) rationing, ( ) patient prioritisation, ( ) euthanasia in the context of resource limitations and ( ) legacy inequalities, discrimination and power imbalances. we conclude with suggestions on how to broaden the debate. we offer neither in-depth articulation, nor resolutions to these concerns. rather, we highlight the value of considering health as a social, cultural and historical phenomenon in addition to a biological one. the complexity of the issues deepens further when we consider the multiple social identities that intersect in the same members and groups within a population. we are confronted with ruefully complex, disturbing, even heartbreaking challenges. yet until the covid- pandemic, these challenges were not openly discussed in the context of palliative care-including in the who guide which is our main focuseven if they were a way of life for many humanitarian and emergency workers and intuitively sensed by individuals external to the sectors. and while satisfactory solutions may not be forthcoming for a long while, we can still debate more openly, think more critically and creatively, and take more of the little steps that allow us to act more compassionately and fairly. we may also acquire greater wisdom and humility, which tend to come with clearer awareness of our limitations in situations where normal life has crossed into chaos. though multifaceted and beyond the focus of our paper, it is important also to have some clarity on what defines or constitutes a humanitarian emergency or crisis. a situation is generally labelled a humanitarian emergency or crisis if international aid is required from donor governments or philanthropic organisations (the alternative is a local or national emergency); and where the humanitarian response comprises the formal system of local, national and international non-governmental organisations, united nations bodies, the international red cross and red crescent societies, military units and international disaster response teams. the types of emergencies and crises the formal and modern humanitarian sector is designed to respond to include conflicts, natural or man-made disasters, disease epidemics and the casualities and mass displacement that may be caused by any of these. crises may be acute or chronic/protracted, and they may be sudden (such as an earthquake) or slow onset (such as a drought). a 'complex' humanitarian emergency is a more recent term to define those emergencies with multiple causes, and which destroy the integrity of whole societies and systems, requiring a system-wide response. poorer countries constitute the majority of humanitarian crises, with their reduced capacity to prepare, respond and recover, although covid- has necessitated an international response in some richer countries, for example, medecins sans frontieres' (msf)'s interventions in italy, spain and belgium. it is our understanding that the who guide intends to speak to humanitarian health workers operating within this formal humanitarian system. bioethics has always engaged with dilemmas at the level of both the individual clinical encounter and the health/illness experiences of populations and groups. some topics, and palliative care is a case in point, reside simultaneously in both subfields. clinical bioethics concerns itself with individual and patients' rights, whereas population-level bioethics includes consideration of the obligations of society to its members as individuals and groups. this shifts the focus from 'the relationship and interactions of individual patients and their physicians' to the social determinants of health, including but not limited to, socioeconomic status, environmental and working conditions, and social exclusion. clinical bioethics stipulates that a just outcome is obtained if an individual's needs are met, while population-level bioethics requires that the needs of the whole population are met. the broader scope of population-level bioethics allows for ethical analyses to consider the extent, direction and distribution of health resources, with special emphasis given to the least healthy populations. the rise of population-level bioethics parallels the rise of population health sciences. the two are underpinned by shared theoretical assumptions about how the world works and how the world should work and the impact this has and will have on the health of populations, groups and individuals. it is thus helpful to consider the defining features of population health sciences in order to contextualise population-level bioethics. the scholarly and practical field of 'population health' has its roots in traditional public health, but is, in many ways, a critical response to the latter's philosophical leanings. valles traces its origin to a reaction against public health, with its heavily biomedical and, by extension, individual-centred approach. population health has developed as a distinct alternative that 'is fundamentally concerned with the social structural nature of health influences, and, although it is embodied in the health outcomes experienced by specific individuals, the domains of influence that shape health experiences transcend the characteristics or circumstances of any one individual'. the biomedical model situates disease and its causes solely within biological, chemical and physical phenomena. it is characterised by a philosophical and methodological reductionism that espouses that the sum is best explained by the parts. such a perspective leads to public health interventions aimed at 'prioritising the development and distribution of drugs and devices that can 'fix' any broken tissue'. intellectual and material resources are disproportionately allocated towards medical interventions as opposed to policies and health interventions that would address the social determinants of health. philosophically, the practice of biomedicine, which relies heavily on the biomedical model, finds its primary underpinnings in deontology; that is, the duty one person has in relation to another in a specific situation. ideally, this does not mean that there is little regard for the good of the population. in practice, however, the good of society is often secondary to the care and advocacy for a specific patient. this narrow conceptualisation of deontology translates well in the context of individual clinical encounters but fails in areas of work focused on the entire population. a broader application of the deontological model, one that assumes that populations should operate based on rules and intent, still falls short of the needs of ethical decisionmaking about population health. rules are stringent and inflexible. alone, deontology does not allow sufficient room for the tradeoffs that must be considered to maintain population health. the biomedical model is also compatible with a utilitarian framework. within the latter, the goal of public health is to achieve the 'good' for the majority of the individuals within a population. indeed, bioethicists have argued that it is utilitarian justifications that underlie public health interventions, more specifically, paternalistic interventions aimed at altering behaviour to maximise the overall good. utilitarian principles are frequently considered the most rational and intuitively 'right' at the level of population health, even if acknowledged as hard, potentially excruciatingly so, to apply vis-à-vis the specific individuals whose well-being or lives are sacrificed in their application. less conspicuously, utilitarianism operates under the assumption that the health of the population is simply the sum of the health of its individuals, with no consideration for the impact of, for instance, cultural and societal history, power dynamics or social status. if health is socially patterned, and there is overwhelming evidence that it is, we should expect unjust differences in health among subgroups based on social identity (eg, race, gender, nationality, etc) and work to eliminate these differences. a utilitarian framework that prioritises the 'utility' or 'health of the majority' may do very little to eliminate health disparities. the goal of population health is to reduce and eliminate health-related gaps between groups. as a result, the discipline does not concern itself with either individual 'duties' or overall utility but with equity. the inclusion of equity mandates that particular attention is paid to the importance of individual, familial, cultural and societal history, as each of them separately and all of them together can result in different 'starting points'. the focus is on health and on social, environmental and biological factors that influence health as opposed to healthcare (care for the ill). additionally, as 'individual health and population health dynamically and mutually affect each other over a gradual passage of time', the shifts of focus from individuals to populations and vice versa are a key analytical pattern. unlike traditional paternalistic public health, population health also advocates for unprecedented multidisciplinary and cross-sector collaboration. importantly, the weight it gives to the lived experiences and resources of citizens and communities is on a par with that given to scholars or organisations. respect for persons ► all patients' dignity and human rights must be respected. ► health professionals should provide patients with all health-related information, respect their decision-making and provide appropriate recommendations. ► patient's health-related information should remain confidential. non-maleficence ► health professionals should only pursue interventions that provide more good than harm. ► all patients should have access to palliative care to minimise suffering. expectant patients should only receive palliation. ► never discriminate on the basis of ethnicity, religion, gender, age or political affiliation. ► avoid complicity with torture (political ethics?) beneficence ► work to provide the patient with the most good by meeting their physical, psychological, social and/or spiritual needs. ► anticipate and prevent future suffering. ► protect from violence and coercion (political ethics?) ► show great judiciousness when the good of the patient or family may be in conflict with the public good (eg, infectious diseases). justice ► similar patients should be treated similarly regardless of ethnicity, religion, gender, age or political affiliation. ► vulnerable patients may require more intensive services. ► health providers and aid workers may require increased health services due to added risks and burdens (principle of reciprocity). ► patient's autonomy should never be restricted unless for the greater good. solidarity ► a community, including the global community, should stand together to face common threats and overcome pathogenic inequalities. (political ethics?) non-abandonment ► medical care should be provided to all needy patients. ► expectant patients must be provided with palliative care. double effect ► an action intended to bring about a good outcome (alleviation of pain) is permissible despite the possibility of a harmful outcome (hastening death). the reason for undertaking such high-risk action must be grave (misuses of science?). statements in bold and italics refer to those that show an implicit concern for the health of populations and groups. statements in bold refer to those that are fully consistent with a perspective concerned with groups and populations. population health arguments typically revolve around a complex tension between two groups, for instance, high-risk versus low-risk, oppressed versus privileged, high-income versus lowincome groups. population health also acknowledges that, within a population, subgroups may require different resources for equity to be achieved, as subgroups too may be starting from vastly unequal innate and acquired resources. in light of the above, the goal of population-level bioethics can be construed as to investigate tensions between and within populations which result in inequitable health outcomes, and to uncover ethical solutions to health-related challenges which are equitable to all members of the population. unlike deontology or utilitarianism, population-level bioethics is not a moral framework, which prescribes the right type of action to be carried out. rather, it is a set of guiding questions and considerations that support actors in engaging critically with the health tradeoffs inherent in any society. these questions and considerations only become apparent when we take a perspective which allows us to identify previously unseen tensions between groups. once such a tension is pinpointed, a deontological or consequentialist (utilitarian) approach can be used to explain or rectify disparities between the groups that comprise the population. the 'right action' can then be, for instance, the implementation of structures and processes that eliminatein the short, medium and long terms-as many unjust health disparities between groups as possible. a distinguishing feature of population-level bioethics is that it does not stipulate that all persons within a population are subject to the constraints of a specific moral framework. rather, within a population, multiple moral frameworks may need to be applied simultaneously to achieve fairness. an additional requirement of population-level bioethics is thus to recognise and at times harmonise conflicting moral frameworks so that they may work together for the good of population health. table represents schematically the standing of population-level bioethics relative to deontology and utilitarianism. in the who guide, ethical issues are approached in a principlist fashion, consistent with a clinical bioethics framework. the seven principles addressed in it and the particular ways in which they are conceptualised are summarised in table . the guide also devotes a brief section to issues around 'ethics and culture', namely matters of unconscious biases, cultural values, stereotyping and human rights. to address clashes of prima facie duties or 'when there are two or more conflicting moral imperatives, neither of which takes clear precedence, and when obeying one imperative would result in transgressing another', the guide recommends ( ) inclusiveness ( ) communication ( ) transparency ( ) accountability ( ) consistency and ( ) ensuring comfort. finally, although the word 'euthanasia' is never explicitly mentioned, brief references in chapters and are made to 'hastening death' as unintentional, be it potentially foreseeable, outcome of attempts to ensure comfort in cases of 'severe, refractory symptoms in a patient with a terminal illness or mortal injury'. table summarises the ethical principles advanced by the who guide. bullet points in bold and italics represent principles underpinned by an implicit concern for groups and populations. 'normal' sentences represent principles that are solely clinical in nature (concerning the care for individual patients). principles in bold are consistent with a population-level bioethics lens. principles which seem to fall outside of both these frameworks are annotated with a question mark and a conjecture of the most proximate ethical debate, not least in view of the political context in which the guide was prepared (eg, political ethics?). four of the seven principles advanced by the guide-respect for persons, non-maleficence, beneficence and non-abandonmentare conceptualised partly with a clear focus on individual patients and individual clinical encounters, partly with a reference to a generic 'all'. the latter inclusion of the entirety of a population, however, remains at this minimalist level, as if the complexity created by that 'all' can be fully resolved through the rules pertaining to the 'one'. no attention is given, for instance, to potential tensions between the needs of individual patients, as arising from resource limitations and/or other socioeconomic and historical determinants of health. two of the remaining principles, justice and solidarity, are likely to require attention to population-level issues, as the presence of 'others' is an implicit or explicit element of their definitions (and those others will often belong to groups or subgroups, as per the concerns of population-level bioethics). yet the principle of solidarity is only couched in terms of a community, including the global community, facing threats together and taking a stance against inequalities. the principle of justice is specified mostly in terms of non-discrimination and priority treatment based on need, with no recognition for the sometimes insurmountable challenges their practice may encounter, as arising from systemic socioeconomic issues or resource constraints. finally, while the principle of double effect is framed in a generic way, it is specified through examples which focus on palliative care for individual patients. the limitations of the ethical debate in the who guide were, perhaps, a direct consequence of the limitations of the broader literature it could draw on at the time of its writing. while texts on palliative care in humanitarian contexts which also raise ethical issues and tensions are, in the current covid- context, multiplying daily (for a collection, see, for instance, ref. ), this was a severely underexplored topic before the current pandemic. previously, the state of the ethical debate on palliative care in humanitarian contexts was most prominently covered in a section of a broader systematic review by nouvet et al. the articles examined in the review raised issues around care for terminal patients, vulnerable populations, moral distress among providers, euthanasia and the tension between allocating resources for salvageable and nonsalvageable patients. a number of stakeholders had been stepping in to fill this void even before the covid- pandemic. for instance, elrha ( elrha. org), a global charity 'that funds solutions to complex humanitarian problems through research and innovation' funded a project by the humanitarian health ethics team-a multidisciplinary research team led by researchers at mcmaster and mcgill universities-to 'develop evidence clarifying ethical and practical possibilities, challenges, and consequences' faced by humanitarian organisations in the provision of palliative care and then create relevant guidance on the basis of it. palliative care in humanitarian aid situations and emergencies (palchase), a network serving as the current focal point for advocacy and debate about palliative care in humanitarian contexts, has also been committed to elucidating associated ethical issues. yet many of the above initiatives were only just underway, with their evidence and guidance still forthcoming. the covid- pandemic has triggered new levels of critical thinking and associated solutions around ethical issues and the place of palliative care, as least in rich country contexts. yet the specifics of pre-existing humanitarian contexts have hardly been addressed. much of the ethical debate which at some stage involves palliative care is focused on rationing and allocation of critical treatments such as ventilators and intensive care bedsunlikely considerations in many parts of the world where such high-cost treatments are not available. in what follows, we aim to contribute to this scarce but rapidly evolving debate by taking a population-level bioethics perspective and addressing issues of rationing; patient prioritisation; euthanasia in the context of resource limitations; and legacy inequalities, discrimination and power imbalances. when considering the equitable access to palliative care across the many different subgroups which comprise a population, we need to take into account the pre-existing resources available within a society as a whole. on the one hand, this defines what is equitable, while being achievable enough, within a particular society. on the other hand, it brings to the fore inequalities and injustice across societies that need to be addressed at a higher level. a framework of 'stuff ' (medication, equipment), 'staff ', 'space' and 'systems' [ ] [ ] [ ] has gained popularity in describing resource needs for palliative care during an emergency. here, we focus on resource limitations concerning stuff and staff. we first consider them at a broad societal/population level (against the background of expectations in the who guide), before looking into the implications such resource limitations have for tradeoffs between groups and subgroups within a population. the who guide recommends that palliative care services, with a specific emphasis on the provision of medication for pain relief and symptom control, be made available to everyone who may need them in humanitarian emergencies and crises, regardless of triage status. since who declared the covid- outbreak a global pandemic ( march ), even some high-income countries have experienced or are experiencing drug shortages. palliative care drugs are also used in intensive care units (icu). competition for these drugs has been reported as one of the reasons for a change of palliative care plans in a swiss hospital near northern italy. shortages of sedatives and drugs for the management of breathlessness have been commonly reported in the usa. the search for creative solutions, not devoid of other agendas, has even led to appeals to us death penalty states to release medications stockpiled in correctional facilities. even when no country-level drug shortages have been apparent (eg, in germany), national authorities have issued guidance against stockpiling to avoid the risk of shortages arising in some parts of the system from overpreparation in other parts of it. in a global supply chain, loss of drug production capacity in certain countries (as in china or italy in the current crisis), trade wars and national bans aimed at ensuring supply for one's own citizens can further limit the availability of drugs-for palliative care as for any other type of need-at critical timepoints. in the previous infectious disease crisis parts of the world where citizens have endured (and continue to endure), the ebola epidemic, the lack of morphine for pain relief has been well documented. the lesson seems to be currently repeated though, arguably, in part because ebola has not wreaked havoc on the developed world. the covid- pandemic may imprint such drug shortages in new and powerful ways on a global scale. the ambition of providing medication for pain relief and symptom control to everyone who may need them in humanitarian emergencies and crises is, however, up against vast inequalities in palliative care globally, as argued for persuasively in a lancet commission report. the need for improvement is particularly acute in low-income countries. between the years - , only . % ( . out of . metric tons) of morphine-equivalent opioids were distributed in lowincome settings. some of the key factors contributing to such gross global inequalities and unmet need are deep seated and/ or emotionally charged, such as unwarranted attitudes towards medically indicated opioid use; inequity in the global pricing of opioids; and advocacy limitations, since terminal patients can hardly engage in relevant activity. the covid- crisis may facilitate future efforts towards removing such roadblocks and improving palliative care services in parts of the world where these are hardly available. but it may also push palliative care further down the list of priorities. for instance, is providing short-term to long-term pain management and comfort care the best way to spend limited funds in humanitarian contexts, where even the basics of survival may be under threat? pain management drugs are inexpensive, as also emphasised by the who guide, yet in a resource-scarce environment, where critical priorities are pitched against one another, more money for drugs may still mean less money for housing, food, clean water and sanitation facilities. moreover, the health professionals who can appropriately prescribe and administer those drugs are not an inexpensive resource. a utilitarian standpoint would support this challenge against palliative care advocates, given that providing adequate nutrition to sustain life, sanitation facilities and clean water to prevent the transmission of communicable disease, and housing to protect individuals from the natural environment will increase population health. this tension is not at all theoretical: unmet needs for food, water, sanitation and hygiene in humanitarian contexts are well documented. even practitioners and staunch supporters of palliative care (as we, in fact, are) may find it hard to argue for pain relief versus bread/rice or water. asserting that we must do our best to meet all those needs does not make the current real-life decisions of funding allocation any less acute. a further question around the (non-specialist) staff who may be expected to deliver palliative care also arises. the physicians and various healthcare professionals of modern medicine believe that, above all, the purpose of their work is to cure. in a medical context, death is typically viewed as a failure. modern biomedicine also seems to be driven by a hubris that it is exclusively dedicated to survival, making the alleviation of suffering 'someone else's problem'. while the unquestioned supremacy of such beliefs needs to be challenged in medical education and healthcare as a whole, we need to work from the fact that most health professionals who are in active practice now, including those working in humanitarian crises or hospital emergency and critical care settings, are trained within similar sets of beliefs. the requirement for the provision of palliative care may then exacerbate the moral distress already prevalent in non-palliative healthcare workers, by imposing a responsibility that conflicts with their reason for being in the field. indeed, some of the most heart-breaking personal stories emerging from the covid- pandemic are those of emergency care clinicians who have chosen their field of work 'to save lives' and are now losing 'battle after battle' like never before. - there is also broader evidence that health providers may feel useless if unable to cure patients. moreover, the boundaries between medical specialties in humanitarian settings and emergencies are far less enforceable. healthcare workers may be reallocated from their specialities and expected to provide palliative care without prior experience and appropriate training. there will be numerous situations where the palliative care team cannot be 'just called in'-and especially so in pre-existing humanitarian crises. the authors of the guide recognise that healthcare workers may experience 'helplessness and distress' due to an inability to alleviate suffering. they also cite 'overworking, overwhelming emotional exposure, hardship in the field, lack of self-care and poor personal management' as reasons for humanitarian workers' burnout. however, they do not consider the possibility that the two might reinforce each other when palliative care services begin to be incorporated in the humanitarian and public health emergency response. the who guide recognises that essential palliative care drugs such as morphine are scarce in humanitarian situations. it too includes the lack of morphine during the ebola outbreak of - as an example of that scarcity. yet the authors seem to consider this a state of affairs that can easily be changed, since the legal basis is there-namely, the exceptions in international drug laws that govern the import and export of narcotics during emergencies. historically, the baseline amount of global narcotics is quite low. as the above examples of drug shortages and some of their explanations (such as competition with icu needs or loss of drug production capacity in key country producers) have begun to demonstrate, even high-income countries may struggle to achieve adequate supply. even if improvements in baseline availability and preparedness happen with phenomenal efficiency, there will be transition periods and contexts where pain medications are, indeed, a scarce resource. how should pain medications be prioritised then and to whom ? in the who guide, palliative care is all encompassing. it is provided to patients regardless of triage status. however, when resources are scarce, it is inevitable to categorise patients and limit care to only some categories of these. when it comes to any form of life and death situation handled with limited resources, the primary dimension of categorisation is uncompromisingly clear: those who will survive and those who will not. using the principles provided by the guide, there is no clear answer whom to prioritise for palliative care. victims of emergencies with non-survivable diseases and injuries may take days to weeks to expire. is it right to continuously provide such patients with pain medication and comfort care while depriving of these patients who may survive? or, should we allocate all pain medications and personnel towards those who are likely to survive in order to increase their current and subsequent quality extended essay of life? the authors of the guide are adamant that palliative care is second only to life-sustaining measures. based on this logic, if human and material resources are scarce, those patients triaged as expectant will not be allocated palliative care resources in order to maximise the quality life years or utility for individuals for whom curative interventions are an option. this conclusion is contrary to the ethical and human imperative to provide care to all patients and practically leads us, full circle, to the point which spurred the movement for palliative care in humanitarian settings in the first place. the authors of the guide do, indeed, state often that society is morally obligated to provide palliative services to expectant patients. in chapter , they remark on the 'false dichotomy' between patients capable and not capable of being saved, insisting that both can receive active healthcare even in situations where resources are overwhelmed. this dichotomy only becomes false if one works under the assumption that resources, even when overwhelmed, are not scarce. such an assumption is not supported by historical and emerging covid-related evidence. we agree that there is a moral duty to provide palliative care to all patients, especially those for whom life-saving interventions are withheld due to scare resources. but the who guide lacks practical guidance on how to distribute this care, and what constitutes a minimum level of care where severe resource constraints exist. finally, the provision of palliative care in humanitarian crises adds a new dimension to the potential conflict between health worker safety and duty of care (non-abandonment). the case of memorial medical center in new orleans, louisiana, provides an example of how quickly and unexpectedly dilemmas around health worker safety and patient abandonment may arise. during hurricane katrina, memorial medical center encountered extreme difficulties in evacuating patients. there were too many people (patients and healthcare workers) and not enough helicopters to transport them. a decision on prioritisation had to be made. it was that the sickest patients and those with do not resuscitate orders were to be evacuated last. regardless of whether we agree with this particular decision or not, we must acknowledge that there are crisis situations when decisions about whom to save and whom to abandon need to be made in minutes, even split seconds, without opportunities for careful deliberation or consulting an ethics committee. in the current covid- pandemic, the dilemma around balancing healthcare worker safety against the duty of care in a palliative care context has reappeared in the care homes of several countries (eg, italy, spain, france, uk). staff in many care homes have not had sufficient personal protective equipment to allow them to care safely for patients dying with covid- . the challenge has been further exacerbated by understaffing due to carers becoming infected and going into quarantine, overlaid onto chronic staff shortages in the sector. [ ] [ ] [ ] as the current pandemic has grown, international aid workers operating in existing humanitarian crises too have been forced to make the impossible decision to stay and deliver much needed assistance to communities; or to leave their positions-and the communities they serve-to avoid confinement, the possibility of facing health risks away from their own families, or not being able to reach family members who may fall ill amidst a world in lockdown. either choice has led to distress for many humanitarian workers. even staying to fulfil the humanitarian imperative brings with it risks of 'doing harm' to communities by spreading the virus. how much should healthcare workers risk their own safety so as to leave no-one behind and/or accompany the dying? should they risk dying themselves in order to relocate to a safer place patients who are already dying or accompany infectious disease patients in their final hours? if some of those who are dying will be left behind or left alone, what is the right thing to do for them? how do the ethos and practice of palliative care interact with these questions? this brings us to the highly controversial topic of euthanasia, assisted suicide and assisted dying; and the standing, in humanitarian emergencies and crises, of the individuals and groups who may be contemplating such an end to their lives, whether legal or illegal in a particular jurisdiction. euthanasia translates, from greek, as 'good death'. euthanasia and the closely associated phenomena of assisted suicide and assisted dying have an ambiguous relationship to palliative care. in lay understandings, they are not only closely associated, but not infrequently misperceived as aspects of palliative care. at the same time, particularly in countries where euthanasia is illegal, they can be seen as antithetical. a study of declarations on euthanasia/assisted dying by inbadas et al found all declarations of palliative care organisations to take a position 'against' (with emphasis on clarifications that a patient's refusal or stopping of treatment, the withdrawal of futile treatment and palliative sedation are not forms of euthanasia). briefly, the argument is that people would not seek euthanasia if they are provided with good palliative care. most recently ( ), the iahpc has stated that no country should consider the legalisation of euthanasia or physician-assisted suicide until it ensures universal access to palliative care services and to appropriate medications, including opioids for pain and dyspnoea. conversations surrounding euthanasia can easily become convoluted. for the purposes of our discussion, we will only focus on how euthanasia interacts with the moral predicaments around resource limitations and patient prioritisation we have addressed so far. we will consider both voluntary and non-voluntary euthanasia, one of the most widespread typologies of euthanasia. voluntary euthanasia is 'where a person makes a conscious decision to die and asks for help to do so', while in non-voluntary euthanasia 'a person is unable to give their consent to treatment (eg, because they are in a coma) and another person takes the decision on their behalf, often because the ill person previously expressed a wish for their life to be ended in such circumstances'. we will also circumscribe the debate by highlighting that euthanasia is not permissible under international humanitarian law. this makes the debate legally theoretical, yet no less acute. in resource-scarce environments, is the right thing to do only to relieve pain? is there a role in such contexts for voluntary or non-voluntary euthanasia and/or assisted suicide to alleviate intractable pain, conserve pain medications and reduce the emotional burden on care providers and loved ones, while also respecting patient wishes? the who guide never explicitly uses the word euthanasia but does endorse providing medication to relieve severe, intractable pain, even if a side and unintentional effect of this may be to 'hasten death'. the intention behind such acts may be the only-and hidden-component which distinguishes them from some forms of euthanasia. the conversation about euthanasia thus hovers above the guide and seems to have deserved direct mention in it. one of the most controversial aspects of that conversation is that, in humanitarian contexts, arguments around the mercy in euthanasia are (perceived to be) entangled with considerations around resource limitations. as discussed, expectant patients may take weeks to days to expire. providing patients with a single, larger dose of barbiturates to enact a decision about euthanasia as opposed to administering small doses to achieve pain relief, over an extended period of time, can conserve medication. this medication can then be made available to others in need, who may not have been prioritised up to that point. while such dilemmas may be prime examples of 'hellish choices', it seems a given that some health professionals and some victims of disasters, no matter how few, have had to face such choices in all their brutality. yet even if a health professional has grappled with such dilemmas in their humanitarian work, as a rule, they would not have ever spoken about them. there are only a few countries (belgium, canada, luxembourg, the netherlands and switzerland, colombia) and a handful of us states and more recently australian states (california, colorado, montana, oregon, vermont and washington, new jersey, and hawaii in the usa; and victoria and western australia in australia) that have legalised euthanasia or assisted dying. as mentioned, euthanasia is not permissible under international humanitarian law. it could be argued that there are conversations to be had of whether the reference points relative to which societies decide on the acceptability and morality of euthanasia still hold fast in extreme humanitarian emergencies and crises, where suffering can take unimaginable proportions. these might also be contexts which demand of palliative care practitioners who are firmly opposed to euthanasia under normal life circumstances to further, or even reconsider, their argumentation. we do not argue for or against euthanasia. we argue that profound unintended negative consequences may follow if we downplay the likelihood that euthanasia-related concerns and dilemmas may arise in new ways for both humanitarians and palliative care practitioners once we begin to integrate consistently palliative care into the response to humanitarian emergencies and crises. these are likely to be further exacerbated for some expatriate humanitarian workers who, on one hand, may be influenced by vastly different beliefs about autonomy and choice in decisions about death and dying than those of local populations and, on the other, will often have no shared language to discuss or decline to discuss such topics. this brings us to our final critique. palliative care is not provided in a vacuum absent of social, economic, geographical, historical, political, cultural and similar interrelated forces, associated with gross inequalities and sources of conflict. if anything, the interplay of these forces is often the very cause of complex humanitarian crises. an article subsection only permits sketchy examples of how such factors may interact with the provision of palliative care in humanitarian emergencies and crises. but we hope that the ones we offer can illustrate how, if initiated incorrectly, palliative care services can inflame deep wounds, aggravating already perilous and precarious situations. to begin with issues of discrimination, there are at least two lines of argument suggesting that we need thoughtful plans to limit discrimination in palliative care in humanitarian contexts, as opposed to broad assertions that we are committed to it not happening. the first stems from discrimination in pre-existing humanitarian contexts; the second from discrimination in palliative care in 'normal life' and in the developed world. in turn, discrimination can take the form of both lack of provision of palliative care for traditionally discriminated groups or provision of palliative care instead of curative care when the latter is available but limited. some discrimination may even be (tacitly) endorsed, both in palliative care and humanitarian settings. such is the case of age. the impulse is often encapsulated in the 'fair innings' argument: older people have already lived enough on this planet; the younger ones have not had the chance. a -member us-based steering committee named the pediatric emergency mass critical care task force remarks (and endorses) that 'if several children can be saved with the resources used to treat one then it is ethically appropriate to favor several over one'. the omission of who the resources are to be taken from creates significant ambiguity, but it is unclear why, if the implied 'one' were not an adult, the statement would be worth making: prioritising the lives of several children over that of a single child would be a standard utilitarian choice, where no matter how excruciatingly difficult the sacrifice is and how many different solutions we attempt before resorting to it, the right thing to do would be hardly debatable, at least in the absence of further considerations. furthermore, the task force remarks on the 'unique attributes' of children, citing increased body surface area-tomass ratio, decreased subcutaneous tissue, decreased herd immunity and decreased cognitive development as reasons children may be categorised as a vulnerable population and, therefore, deserving of special priority. what these authors do not say is that the inclusion of such factors in a triage system will result in children always being prioritised for curative interventions over many adults in humanitarian crises. we have seen the operationalisation of the fair innings argument play out in practice in the current pandemic. the health system in italy, overwhelmed beyond capacity, 'invoked' the argument to justify prioritising younger adults for intensive care services over older, sicker adults. while we may promote cultures of non-discrimination-and we generally accept that we would not discriminate based on gender, age, ethnicity or disability-pandemic triage decisions are, by their nature, broadly discriminatory. even ethical decision-making frameworks currently being developed or used which invoke characteristics other than age, such as quality of life or maximising quantity of life years saved, frequently converge around the exclusion of older people. the empirical evidence on the deprioritisation of older people in humanitarian crises is compelling. during hurricane katrina in new orleans, louisiana, % of the deaths were of individuals over the age of , despite the latter accounting for only % of the overall population. in japan during the tsunami, % of the deaths were of individuals aged and above, despite their accounting for only % of the local population. the disproportionate deaths among older people need not be due to explicit discrimination in triage mechanisms. most humanitarian policies pay lip service to, or do not account at all for, the unique needs of this vulnerable population, for example, through policies addressing transportation to care facilities, nutrition and family separation. with racial discrimination, there is clear evidence of it occurring both in normal times within the developed world, and during times of humanitarian crisis. the mechanisms may be circuitous. during hurricane katrina, residents of new orleans were urged to evacuate by car before the hurricane made landfall. however, black americans, who, at the time, made up % of the population of the city, were over three times more likely not to have access to a vehicle, leaving them vulnerable to disproportionate morbidity and mortality. in the usa, people of african and latin descent are routinely undertreated extended essay for pain [ ] [ ] [ ] and their end-of-life wishes are assumed based on cultural generalisations. in the uk, a study revealed that black caribbeans were less likely to be aware of palliative care as a specialty than their white british counterparts -an example of how structural discrimination can impede equity even before a disaster strikes. there are pre-existing barriers when minority and vulnerable populations attempt to access either humanitarian support or palliative care as well as inequalities in their provision. at the intersection of the two, challenges are at best likely to be replicated and, potentially, significantly augmented. again, covid- has exemplified how a humanitarian crisis can expose pre-existing discrimination and structural racism. in the usa (as of april), black americans accounted for % of covid- hospitalisations and % of deaths (in / reporting states). in the uk, a report of the institute for fiscal studies (may ; the pandemic still ongoing) estimated that 'bangladeshi hospital fatalities are twice those of the white british group, pakistani deaths are . times as high and black african deaths . times as high'. such stark inequities have even prompted us ethicists, to ask if white americans should be deprioritised for critical care services to prevent the structural racism which grants them these life-saving privileges while depriving others. ethnic minority populations are disproportionately marginalised to low-income jobs where exposure to infectious diseases is more likely; and to poorer diets and poorly constructed built environments that are often risk factors for chronic illnesses such as diabetes, obesity and hypertension. in turn, emergent covid- triage and ethical guidelines for critical care services in scarce resource environments deprioritise on the basis of pre-existing conditions, [ ] [ ] [ ] thus further increasing the likelihood that racial and ethnic minorities suffer a higher death toll than the dominant group. if some of the above guidelines are also followed in their otherwise commendable emphasis on providing symptom control and palliative care to patients who have been deprioritised for critical care, then minorities may become overexposed to palliative care as a direct consequence of resource limitations. this would not be any 'fault' of palliative care and its practitioners. the deprioritisation decision too may be genuinely clinical, with no relationship to ethnicity at the point of patient presentation. but the legacy inequality and discrimination based on race and ethnicity will be underpinning the outcomes, and palliative care will be implicated in them. challenges such as the above are also likely to be amplified in middle-income and low-income countries. poor infrastructure, greater disease burden and fewer resources, reflecting the inequitable global distribution of wealth, contribute to higher mortality after an emergency. these also have an impact on the timeliness with which people can access services, which, in turn, has implications for the availability of treatments. if curative interventions are dispersed on a first-come, first-serve basis, once depleted, palliative care services may be the only intervention available. members of populations who faced barriers to arriving first for care may be relegated to palliative services not because of medical indication but, rather, because of social identity. palliative care may thus become a tool for masking and perpetuating inequity. how can we ensure that implicit biases or structural forces such as socioeconomic status do not impede appropriate care, whether curative or palliative, for minority or vulnerable populations in humanitarian contexts? we should also recognise that many middle-income and lowincome countries were once colonised by many of the same countries which provide aid today. in light of global colonialism, what does it look like for respondents from predominantly high-income countries to provide palliative care to persons from middle-income and low-income countries? we cannot assume we have earned the trust of these countries and communities and that all stakeholders will believe that endeavours of palliative care are pure hearted and not, indeed, extermination. during the ebola epidemic in sierra leone, for instance, local people were hiding corpses because they believed that the aid workers were selling the organs of their loved ones. there again, there were rumours that water, sanitation and hygiene teams were poisoning the water when they were chlorinating it; that drug companies were bringing in a disease for which they would then offer an expensive cure; that it was the nongovernmental organization (ngo) workers who were infected with and spreading ebola; and that, overall, 'the white man only turns up when people die, so there must be a link' (personal communication from i jacklin, ). more currently, public health experts speculate that the ebola outbreak in the democratic republic of congo, which is reported as the world's second-worst outbreak, is being fuelled by mistrust and 'community scepticism'. it has been reported that ebola treatment centres were attacked due to such mistrust and beliefs that the continued ebola outbreaks are profit driven (eg, white countries profiting from the illness and death of black bodies). in the current pandemic, un aid workers have been blamed for bringing covid- to south sudan after four of its staff tested positive, triggering xenophobia and the suspension of aid activities, and fuelling existing political suspicion over the presence of the un in the country as interfering with sovereignty. should we be developing policies and programmes to bolster trust in the context of palliative care or, even more generally, in crises with a high death toll from 'invisible' causes? closely intertwined with the above issues are the wide cultural differences in understandings of illness, death and dying which, in turn, shape local practices in caring for and comforting the sick or deceased person. how can we ensure that we learn our lessons, again from the ebola outbreak of - , when western values and practices of safety and public health clashed with local values and rituals around death and bereavement, each of them not only natural, but non-debatable, in the minds of those who held them? in many west african communities, local burials included a washing ceremony -a procedure that readily transmits ebola. who reported that % of the ebola cases in guinea during the outbreak were related to burial practices. precisely to minimise the risk of transmission, aid teams performed rapid burial ceremonies without familial notification. this bred contempt and mistrust. we are already witnessing the transformation of grieving and funeral practices across the world where covid- social distancing rules are being enforced. it is critical that we acknowledge local rituals around death and bereavement as covid- spreads and seek to build support among communities, religious leaders and funeral homes for adaptations to such rituals which are both compassionate and adhere to necessary infection control. finally (though only within an initial set of contextual considerations as opposed to a systematic list of these), a populationlevel view also begins to identify the contribution of local actors, such as health workers or family members, who are usually the first responders in a humanitarian emergency. local actors provide crucial care in the form of immediate and long-term practical and emotional support and simply sharing space with those who are suffering. it is nothing but a prejudice not to account for their extraordinary contributions to comforting the ill and dying and alleviating suffering. it is vital to consider how to integrate the resources of international humanitarian actors into existing care for the seriously ill and dying provided by local communities. as the globalisation of our world increases, we will be witnessing, experiencing and shaping more and more of its opportunities and abundance, of its challenges and tragedies together. this includes our humane and humanitarian response to alleviating the pain and suffering of the dying and terminally ill. who guidance on the integration of palliative care and symptom relief in humanitarian response is and will continue to be key to enabling what is a moral imperative, even if the covid- pandemic has been a too ferocious testing ground for its recent manual on the topic. it is of little value, apart from unpalatably righteous, to belabour the critical aspect of our argument. we hope that our paper will serve primarily as a source of ideas on improving successive documents on palliative care in humanitarian emergencies and crises. the core argument we have advanced is that applying a population-level ethics lens to the provision of palliative care in humanitarian settings brings up a whole host of ethical challenges that have been missed by an over-reliance on a predominantly clinical bioethics lens. we also suggest a range of considerations not captured by the utilitarian perspective-our default moral framework for when the good of the community needs to take priority over the good of the individual. the addition of a population-level ethics lens is in no way sufficient for illuminating all ethical dilemmas falling outside the visual field of clinical bioethics. population-level ethics is only one of many perspectives we need to incorporate in a robust and relevant ethical analysis of palliative care in humanitarian emergencies and crises. another type of analysis which should receive urgent priority is that informed by humanitarian ethics. the latter can offer unique insights about, for instance, the intersections between the personal and the political and between the intimate, the operational and the strategic. as slim asserts, 'it is in the realm of politics that humanitarian ethics finds its natural habitat and not simply the realm of medicine, nutrition, sanitation, economics or social work that make up the various fields of its practice. doing humanitarian work at scale is doing politics'. humanitarian ethics is, crucially, multilevel ethics: the intimate, where humanitarian workers such as doctors, engineers or social workers support individuals, and families and communities, acting in an individuals' best interests to alleviate suffering; the operational, where humanitarian managers need to make ethical decisions about areas of operation to support populations within camps, districts and regions (this level is likely to involve questions about resource allocation and political questions concerning cooperation with governments, other ngos and sometimes armed groups); and the strategic, where leaders of humanitarian organisations must make global choices around funding, geographical and sectoral priorities and political partnerships, concerned with institutional interests and goals. it is easy to see how neither clinical bioethics, nor population-level ethics can offer sufficient insights into the operational and strategic levels of humanitarian ethics, both for the humanitarian health response in general and for strands of it addressing the needs of the seriously ill and the dying in particular. the perspectives of disciplines such as anthropology, crosscultural psychology, legal studies, sociology, history, social geography, colonial and postcolonial studies, and political science can further advance the relevant ethical debate. for instance, ethical issues around opioid dependency, and the legal regimes associated with them, are a widely debated problem but one which we deprioritised so as to bring out more acute blind spots. additional ethical issues can be identified, of course, by practising humanitarians and the recipients of their support. there must also be oft-forgotten perspectives which too can be exceptionally illuminating, such as those of interpreters and drivers, the often invisible intermediaries in humanitarian settings. beyond upholding the importance of a much richer ethical debate, we have also been arguing, be it largely indirectly, for a greater honesty and humility in it. it is important to have documents which outline and promote a positive vision. but when that vision is too distant from current and contextually diverse realities, such documents become irrelevant, even deserving of cynicism. it is particularly incomprehensible when this happens with regard to palliative and end-of-life care-a field defined by its ability to face some of the darkest and most frightening aspects of life and still preserve our hope and humanity. we hope this paper can stir a debate among a broad variety of stakeholders, for the benefit of all whom we cannot save during humanitarian crises and who are experiencing grave suffering, whether physical, emotional, social or spiritual. and while only a small proportion of us will work firsthand to alleviate such suffering, most of us are its (distant) observers and, without exception, its potential victims. we cannot be looking away. twitter keona jeane wynne @keonawynne contributors all authors contributed equally to this work. funding the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. disclaimer the views expressed in this paper are rc's and mp's views as an academic researchers and not a formal position of palchase. competing interests mp reports that she is a steering group member of palliative care in humanitarian aid situations and emergencies network. rc reports that she is a member of the palliative care in humanitarian aid situations and emergencies network. patient consent for publication not required. provenance and peer review not commissioned; externally peer reviewed. this article is made freely available for use in accordance with bmj's website terms and conditions for the duration of the covid- pandemic or until otherwise determined by bmj. you may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. palliative care considerations in mass casualty events with scarce resources taking seriously the "what then?" question: an ethical framework for the responsible management of medical disasters should palliative care be a necessity or a luxury during an overwhelming health catastrophe? palliative care in humanitarian crises: always something to offer alleviating the access abyss in palliative care and pain relief-an imperative of universal health coverage: the lancet commission report palliative care in complex humanitarian crisis responses a field manual for palliative care in humanitarian crises. a field manual for palliative care in 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program directors covid- -ethical issues. a guidance note palliative care considerations in mass casualty events with scarce resources the elephant in the room: collaboration and competition among relief organizations during high-profile disasters families in liberia are paying bribes for false certificates over ebola deaths how the fight against ebola tested a culture's traditions tackling congo's ebola outbreak "more than a public health response. new humanit the new humanitarian | what's behind south sudan's coronavirus inspired unbacklash the impact of traditional and religious practices on the spread of ebola in west africa: time for a strategic shift a good death" during the covid- pandemic in the uk: a report on key findings and recommendations coronavirus is changing how american muslims hold funerals | middle east eye humanitarian ethics : a guide to the morality of aid in war and disaster key: cord- -ezf r l authors: jawad, a.j. title: effectiveness of population density as natural social distancing in covid spreading date: - - journal: ethics med public health doi: . /j.jemep. . sha: doc_id: cord_uid: ezf r l recently, many countries have decided to reopen gradually and some of them have thought that social distancing has not had a significant effect. in our study, a new view of the importance of social distancing to prevent the spread of coronavirus has been presented in terms of the relationship between peak day and peak period and population density of nine countries. data for nine different countries in different coronavirus situations have been analyzed. the analysis process was applied by using three programs, namely; webplotdigitizer, wsxm and origin. the results provide evidence of the effectiveness of social distancing by calculation of the effect of population density on coronavirus infection. that was applied by two stages, the first one by determination of two different groups of countries depending on the rate and range of coronavirus spread. these two groups were countries with developed and developing covid which lead to calculate the peak day and the period times of developed groups. then, analysis of that data with population density was evaluated to indicate there are significant effects of population density on peak day and peak period times which explain the importance of social distancing between people to manage and control that. the results showed that there are increasing in peak day and peak period times with increasing the population density. analysis of that data with population density was evaluated to indicate there are significant effects of population density on peak day and peak period times which explain the importance of social distancing between people to manage and control that. the results showed that there are increasing in peak day and peak period times with increasing the population density. © published by elsevier masson sas. coronavirus ; covid ; jour de pointe ; période de temps ; densité de population ; distanciation sociale résumé récemment, de nombreux pays ont décidé de rouvrir progressivement et certains d'entre eux ont estimé que la distanciation sociale n'avait pas eu d'effet significatif. dans notre étude, une nouvelle vision de l'importance de la distanciation sociale pour prévenir la propagation du coronavirus a été présentée en termes de relation entre le jour et la période de pointe et la densité de population de neuf pays. les données de neuf pays différents, dans des situations différentes en matière de coronavirus, ont été analysées. le processus d'analyse a été appliqué en utilisant trois programmes, à savoir : webplotdigitizer, wsxm et origin. les résultats fournissent la preuve de l'efficacité de la distanciation sociale par le calcul de l'effet de la densité de population sur l'infection par le coronavirus. cette méthode a été appliquée en deux étapes, la première consistant à déterminer deux groupes de pays différents en fonction du taux et de l'étendue de la propagation des coronavirus. ces deux groupes étaient des pays avec des covid développés et en développement, ce qui a permis de calculer le jour de pointe et les périodes des groupes développés. ensuite, l'analyse de ces données avec la densité the previous recording of influenza pandemics proves that stockpiles of antiviral drugs will be limited to amounts, which can be used mostly for treating the critical cases of influenza. on the other hand, social distancing is one of the most important non-pharmaceutical interventions (npis) [ ] , widely applied by health services to minimize influenza spread in society, which has three obvious benefits. the first positive point would be to delay the date of the infection peak to allow more time for healthcare teams; the second point is to minimize the volume of the epidemic peak profile; and the last one is to make the infection distributions over a longer period of time which enables more significant management of these issues and more potential for drugs to be applied [ ] . infections by viruses, such as covid , are believed to spread more through close contact in homes, workplaces, schools and public places, and especially in crowded and busy cities and countries [ ] . predictive, mathematical and statistical models for epidemics like covid [ ] are important and fundamental in terms of understanding the epidemic and planning effective ways to control it. there are many models that have been developed to use in the case of the covid- pandemic, lin and his colleagues extended a seir (susceptible, exposed, infectious, removed) model by considering the risk perception and the cumulative value of cases [ ] , anastassopoulou and his colleagues suggested a discrete-time sir model which covers dead individuals [ ] , casella proposed a control-oriented sir mathematical model which includes the delay effecting and compares that between different containment strategies [ ] and wu and his colleagues applied transmission dynamics concepts to calculate the clinical activity of covid- [ ] . in fact, lock-down and social distancing restrictions could lead to poverty and in some cases to undernutrition, educational weakness and undo enhancements in access to health services which have been achieved in the last few years [ ] . in our work, we try to analyse the relationship between population density and sizes on covid spreading in the terms of peak day and period times in nine different countries. fig. shows the steps of methodology of the chose and the analysis for nine different countries in detail. choose nine different countries roughly and analyzed their data as shown in fig. . it can be seen that the first stage is going to the website of johns hopkins university [ ] to choose the countries randomly in the form of a picture by utilizing the snipping tool. then, this picture will convert to data by using webplotdigitizer and save it in the excel form for the next step. after that, the data will change to a smooth curve by using wsxm and save it in the form of picture again. depending on the form of the curve, these curves will be divided into two types; with a peak, which represents developed countries and without a peak, which represents developing countries. the first group will convert again to data in the form of an excel file which will plot as a curve by using origin. analysis and fitting of data will be applied by that program to calculate the peak point data analysis, which will be used next in the model analysis. otherwise, the second group of curves will pass directly to the general model to predict and calculate the peak point. the most important five steps in the analysis of data are reported in the first in fig. . the figure shows the first analysis stage is taking a picture by using the snipping tool. then, this picture converts to data in the form of an excel file using webplotdigitizer in stage two. after that, that data has to change and to smother curve by utilizing of wsxm in stage three. depending on the last stage, these curves will be divided into groups as we mentioned in fig. , the first one that has a peak point, while the other does not. if the curve has a peak point, it will be saved. then, this curve will be converted into data by using again webplotdigitizer in stage four and finally it will be changed into a curve and analysed to produce the model by origin in stage five. on the other hand, curves that do not have peak point will be calculated and predicted by the determined model. the main five steps of each country in our work are presented in figs. - , which represent china, france, germany, iran, iraq, italy, spain, the united kingdom and the united states, respectively. in each figure, there are five curves which show the mentioned five steps in fig. , which are calculated until may . the main goal of these five steps is calculation of period and date of peak to analyse that with the population size of these countries in the next stage. generally, it is clear that china, france, germany, italy and spain belong to the developed coronavirus group because they have and show a peak point, while iran, iraq, the united kingdom and the united states belong to the developing group. for the developed coronavirus countries group, fig. shows the peak point was after days for china and the period time of the peak was days, while figs. and illustrate the peak points were after and days for france and germany, and the period times of peak were and days, respectively. in figs. and , the peak points of italy and spain were after and days, respectively, while the period times of the peak was days for them. on the other hand, figs. , , and show that iran, iraq, the united kingdom and the united states do not have a peak point. the relationship between the dates of peak days, novel coronavirus daily cases, peak period times, the ratio of peak period times and the dates of peak with the density of population per square mile are shown in figs. - , respectively, for five different countries which are regarded as developed coronavirus countries. the countries are france, china, italy, spain and germany which have the density of population per square mile about , , , and , respectively [ ] . it is clear that the peak day decreases with increasing the density of population. however, there are increases in the peak day in the range of density of population between - million per mile square. that is may be due to the random distribution of population and the high age level of italy, as an example. novel coronavirus daily cases increases with increasing the density of population because the social contact will be more likely and the infection rate will be higher. it seems that italy has lower point compared to the other four countries. that may be because of high restricted procedure applied by the government which also explains why it has a higher peak point in fig. . fig. provides evidence about the increasing of peak period times as the population density increases. this happened as we have mentioned and discussed in the last figure, because the high density of population leads to a higher incidence of contact between people and makes social distancing less feasible. the relationship between the ratios of peak period times to peak day with population density shows significant effects on of these parameters. where there are increases in that ratio with increasing population density, the number of people in specific areas will be higher. that number encourages a higher level of infection as a result of minimizing social distancing between people. this work provides evidence of the effectiveness of social distancing by calculation of the effect of population density on coronavirus infection. that was applied by two stages, the first one by determination of two different groups of countries depending of the rate and range of coronavirus spread. these two groups namely developed and developing covid which lead to calculate the peak day and the period times of developed groups. then, analysis of that data with population density was evaluated to indicate there are significant effects of population density on peak day and peak period times which explain the importance of social distancing between people to manage and control that situation. generally speaking, the results showed that peak day and peak period times rise with increasing the population density. nonpharmaceutical measures for pandemic influenza in nonhealthcare settings --social distancing measures effectiveness of workplace social distancing measures in reducing influenza transmission: a systematic review nonpharmaceutical measures for pandemic influenza in nonhealthcare settings --international travel-related measures modelling the covid- epidemic and implementation of population-wide interventions in italy a conceptual model for the outbreak of coronavirus disease (covid- ) in wuhan, china with individual reaction and governmental action data-based analysis, modelling and forecasting of the covid- outbreak can the covid- epidemic be managed on the basis of daily data? estimating clinical severity of covid- from the transmission dynamics in wuhan, china response strategies for covid- epidemics in african settings: a mathematical modelling study covid- coronavirus pandemic world population stabilization unlikely this century i would like to express all my deep thanks and respect to mr. james morgan (a member of twin group, the greenwich centre, lambarde square, greenwich, london, the uk) for his help and cooperation in this work. the author declares that he has no competing interest. key: cord- -d ku dyz authors: wang, w.; wu, q.; yang, j.; dong, k.; chen, x.; bai, x.; chen, z.; viboud, c.; ajelli, m.; yu, h. title: global, regional, and national estimates of target population sizes for covid- vaccination date: - - journal: medrxiv : the preprint server for health sciences doi: . / . . . sha: doc_id: cord_uid: d ku dyz abstract background covid- vaccine prioritization and allocation strategies that maximize health benefit through efficient use of limited resources are urgently needed. we aimed to provide global, regional, and national estimates of target population sizes for covid- vaccination to inform country-specific immunization strategies on a global scale. methods based on a previous study of international allocation for pandemic covid- vaccines, we classified the entire world population into eleven priority groups. information on priority groups was derived from a multi-pronged search of official websites, media sources and academic journal articles. the sizes of different priority groups were projected for countries globally. results overall, the size of covid- vaccine recipient population varied markedly by goals of the vaccination program and geography. the general population aged < years without any underlying condition accounts for the majority of the total population ( . billion people, %), followed by . billion individuals at risk of severe disease, and . million essential workers which are critical to maintaining a functional society. differences in the demographic structure, presence of underlying conditions, and number of essential workers led to highly variable estimates of target populations both at the who region and country level. in particular, europe has the highest share of essential workers ( . %) and the highest share of individuals with underlying conditions ( . %), two priority categories to maintain societal functions and reduce severe burden. in contrast, africa has the highest share of healthy adults, school-age individuals, and infants ( . %), which are the key groups to target to reduce community transmission. interpretation the sizeable distribution of target groups on a country and regional bases underlines the importance of equitable and efficient vaccine prioritization and allocation globally. the direct and indirect benefits of covid- vaccination should be balanced by considering local differences in demography and health. background covid- vaccine prioritization and allocation strategies that maximize health benefit through efficient use of limited resources are urgently needed. we aimed to provide global, regional, and national estimates of target population sizes for covid- vaccination to inform country-specific immunization strategies on a global scale. based on a previous study of international allocation for pandemic covid- vaccines, we classified the entire world population into eleven priority groups. information on priority groups was derived from a multi-pronged search of official websites, media sources and academic journal articles. the sizes of different priority groups were projected for countries globally. overall, the size of covid- vaccine recipient population varied markedly by goals of the vaccination program and geography. the general population aged < years without any underlying condition accounts for the majority of the total population ( . billion people, %), followed by . billion individuals at risk of severe disease, and . million essential workers which are critical to maintaining a functional society. differences in the demographic structure, presence of underlying conditions, and number of essential workers led to highly variable estimates of target populations both at the who region and country level. in particular, europe has the highest share of essential workers ( . %) and all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint as coronavirus disease continues to spread across the world, more than candidate vaccines for covid- are in development and candidates have entered in phase iii clinical trials as of september , ( ) . hopes are high to bring one or more vaccine candidates to market by the end of the year. despite . million cases reported so far ( ) , most of the world population still remain susceptible -an increasing number of seroepidemiological studies are finding low seroprevalence of antibodies to sars-cov- , in the range . %- . % ( ) ( ) ( ) , although higher incidences were reported locally [e.g., ~ % in new york city, ny, usa ( ) ]. as such, a large demand for covid- vaccine is expected in the next year. manufacturers has revealed that the global production capacity is estimated to be ~ . billion doses annually ( ) . thus, given a two-dose vaccination schedule which is planned for the majority of current covid- candidates, current annual production capacity ( ) will be too limited to achieve herd immunity by immunizing %- % of the global population. as such, defining a prioritized vaccination program will be necessary. there are important questions about equitable and efficient distribution of covid- vaccine as many low-and middle-income countries lack covid- vaccine research, development and production ( ) . to bring the pandemic under control via equitable access to covid- vaccines, covax, the vaccine pillar of the access to covid- tools (act) accelerator, has been established with global all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint cooperation to ensure availability to both higher-income and lower-income countries ( ) . in addition, given the likelihood of an initial period of vaccine shortage, country-specific interim frameworks for covid- vaccine allocation and distribution have been developed by experts in the united states ( , ) and united kingdom ( ) . however, information is lacking about the number of vaccine doses that each region and country needs. this will hamper the equitable and efficient allocation and distribution of covid- vaccine. here, we provide global, regional, and national estimates of the size of the covid- vaccine recipient population by priority group under the allocation frameworks proposed by various international teams ( , ( ) ( ) ( ) . the vulnerability of each country to covid- is based upon factors such as geographical location, disease burden, the likelihood of an outbreak and the potential for subsequent severe public health impacts. priority groups can be categorized into different allocation tiers according to country-specific pandemic characteristics and vaccine objectives. estimates of target population sizes can guide relevant stakeholders in the development of fair and equitable global allocation strategies and inform vaccination programmes tailored to the local specificities of each population. previous proposals for the international allocation for pandemic covid- vaccines have endorsed three fundamental objectives ( , ( ) ( ) ( ) : ) maintaining essential core societal functions during the covid- all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint pandemic, such as essential health services and food delivery; ) protecting people from irreversible and devastating harm, such as death and severe covid- disease that causes long-term organ damage (e.g., lung, kidney and liver); ) controlling community transmission, enabling a return to normal prepandemic economic and social activities. the importance of maintaining essential core societal functions has been highlighted in the context of covid- pandemic, and the concept of essential workers has already been extended beyond health-care personnel ( ) . in light of previous proposals, these include, but are not limited to, workers in the food industry and domestic transportation, police and military staff who maintain public safety, as well as workers maintaining electricity, water, fuel, information, and financial infrastructures. regarding individuals who may experience irreversible and devastating harm from covid- , previous reports have identified those older than years of age, those with high-risk health conditions, and those in close contact with people at very high risk of poor outcomes (e.g., nursing home and long-term care facility workers) as target population ( , ) . a third possible vaccine goal is to reduce covid- transmission; in this case, high transmission groups should be targeted. target populations include adults and children involved in economic or educational activity, who experience higher risk of economic or educational harm from not working or going to school, and all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint have a higher probability of transmission when going back to work or school due to increased contacts ( ) . we defined groups of potential vaccine recipients aligned with the three goals of covid- vaccination (fig. ) . first, to maintain essential core societal services, individuals who are essential to maintaining an effective healthcare system (i.e., healthcare workers), national and social security (i.e., police and military), and normal living supplies (i.e., workers in essential infrastructures) need to be given careful consideration for priority. second, to reduce severe covid- disease (i.e., hospitalizations, critical care admissions, and deaths), people with underlying conditions [i.e., cardiovascular disease, chronic kidney disease, chronic respiratory disease, chronic liver disease, diabetes, cancer with direct immunosuppression, cancer without direct immunosuppression but with possible immunosuppression caused by treatment, hiv/aids, tuberculosis (excluding latent infections), chronic neurological disorders and sickle cell disorders] ( ) , those older than years of age without any underlying conditions, as well as pregnant women should be included as a candidate priority groups. considering age-specific susceptibility to sars-cov- infection ( ), we then reclassified people with and without underlying conditions into different groups by virtue of their age, i.e., people aged  or < years-old with at least one underlying condition, people aged  or - years-old without any underlying condition. third, to reduce symptomatic infections and/or to stop virus transmission, vaccination should extend to all individuals younger than years of age without any underlying conditions. these individuals are further reclassified into three all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint groups (i.e., people aged - years-old, those aged - years-old, and those aged - years-old) on the basis of their risk of transmitting virus and economic harm from not working ( ) . to estimate the size of priority groups for vaccination by country, we extracted information from publicly available data sources during - (see tab. s for data sources), including the ) united nations (un) mid-year population estimates for for who member states (and countries/territories); ) country-specific sizes of the military population from the world bank group or searching baidu, bing, and google search engines using the search terms "military size" and world health organization country names; ) the density of physicians, nurses and midwiferies by country from the world bank and the world health organization; ) the number of people working in the electricity, gas, water, steam and air conditioning sectors, food, accommodation, domestic transportation and storage industries, using census data on economically active population in countries; ) the number of individuals at increased risk of severe covid- by age and country from previous report by clark a, et al. ( ) . two independent investigators applied the same search procedure for crosschecking and comprehensiveness. up to ( . %) countries had missing values (see completeness analysis of data in tab. s ) for the number of essential workers who ensure basic life needs. thus, we employed a state-of-the-art multivariate imputation by chained all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in global, regional, and national estimates of each target population were obtained by summing the relevant population group estimates stratified by vaccination goal (see data in tab. s ) . to avoid the overlap between the group of essential workers and adults aged - years without any underlying conditions, we subtracted those engaging in essential work activities from the broader group of healthy adults. moreover, data on age-specific prevalence of underlying conditions were lacking for countries. in the main analysis, we assume that the age-specific prevalence of underlying conditions in countries with missing data is the average of that in countries with available data in the same who region. then, the number of persons with and without underlying conditions at a given age is equal to the prevalence of underlying conditions multiplied by the corresponding population size. in a sensitive analysis reported in appendix, we assume that, when the data on underlying conditions is not available, the number of persons without any underlying condition corresponds the total number of persons of that age. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in in main analysis, to consider vaccine programs tailored the epidemiological situation of individual countries, we also used covid- case counts (as of september , ) and serology data to estimate the size of the population already infected, who may be at lower priority for vaccination. we found data on the number of laboratory-confirmed cases by rt-pcr (n= countries) or serological assays (n= ) from published literature and official reports. (see tab. s ). the number of serologically-confirmed case in a country was measured as the seroprevalence of sars-cov- ( ) multiplied by the corresponding population size. in sensitivity analyses, we excluded this epidemiological information from vaccine allocation estimates. in addition, to account for potential issues concerning vaccine hesitancy and delivery, a sensitive analysis was performed to estimate the size of covid- vaccine recipient population by assuming a vaccination coverage of - % ( ) . the funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. on a global scale, if a universal covid- vaccination program was implemented, the target population would include . billion people (tab. and fig. a) . of all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in geographical disparities are observed in the share of different target population groups across who regions. if we consider the entire population as target for vaccination (no prioritization by occupation or risk group), south-east asia ( . billion, . %) and western pacific ( . billion, . %) together account for all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the size of each target population by age also varies markedly across regions. it is noteworthy that few individuals are over years of age in africa whilst a considerable fraction reside in europe and north america (fig. ) . the workingage population accounts for a substantially larger proportion of the total population than other target populations in all regions. in addition, the share of individuals aged < years of age is relatively high in africa compared to other regions. on a country level, sizable heterogeneity emerges in the distribution of different target population groups, ranging from , people to . billion people (fig. ) . national estimates of the size of target population suggest that seven countries, including china, india, united states, indonesia, pakistan, brazil and nigeria, all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint have a larger share of total target population (fig. ) ; by contrast, countries in africa and eastern mediterranean regions show a relatively lower share of total target population ( fig. and fig. s ). we also found that the target population that maintains essential core societal function is more predominant in middleand high-income countries (fig. and fig. s ) . moreover, between-country variations in the size of target population to reduce severe disease or to contain sars-cov- transmission were observed, with . % of total population distributed in china, india, united states, indonesia, japan, russian federation and brazil (fig. , fig. s and fig. s ). for the eleven countries lacking data on age-specific prevalence of underlying conditions, the obtained estimates of the target populations are robust to changes in assumptions about frequency of underlying conditions (compare tab. s with tab. s ). we determined different target population groups according to goals of the vaccination program (maintain essential societal functions, minimize severe disease, interrupt transmission), and quantified the size of each target group on a global, regional and country level. there are important variations in the amount of vaccines needed depending on the goals of the vaccination program, and the distribution of target populations varies within and between regions. in particular, large demand for vaccines was seen in essential workers and high-risk populations with poor health conditions, with the later accounting for . % of all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in we estimated that approximately . billion doses of a covid- vaccine will be requested by who member states for a universal covid- vaccination program, given a two-dose regimen. assuming all of the vaccine manufacturers with existing candidates can offer vaccines concurrently, the global production capacity of covid- vaccine is estimated at . billion doses annually ( ) . not enough vaccine will be available at the beginning of a covid- vaccination program, even in an optimistic scenario. to achieve herd immunity by protecting at least - % of individuals ( . to . billion), it will take about to months to produce enough covid- vaccines. vaccine supply and delivery all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint services will constrain the roll-out of covid- vaccination programs as well. in this context, the same barriers would apply to all target groups, but vaccination of targeted occupational or high-risk groups will likely be more feasible than the general public without any underlying conditions. this together comprise an estimated . billion people in who member states. within-and between-region disparities in the distribution of each target population highlight different demands for covid- vaccine. these disparities will result in different durations of vaccination program, due to global limitations in vaccine production/supply capacity. for example, in countries with sufficient capacity for vaccine production and supply to meet the national demand (e.g., the united states and china), the covid- vaccination program could last a few months, while it could last much longer in low-and middle-income countries which have relatively lower capacity for vaccine production and delivery ( ) . thus, vaccine allocation plans need to be adjusted accordingly to consider interand intra-regional disparities in the demand for vaccine and capacity for vaccine production/supply. besides direct benefits (i.e., protection from infection, reduction in illnesses and mortality rates), vaccine prioritization and allocation should also balance indirect benefits that can reduce virus circulation in a community, as vaccinated individuals are less likely to be infected and transmit the virus ( ) . in particular, indirect benefits may be important to protect individuals aged > years of age who are at increased risk of severe disease and also possibly less likely to be directly protected by vaccination due to immune senescence ( ) . all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in we were unable to collect data on population stratified by occupation in . % of the countries considered. excluding those from the analysis would lead to the exclusion of a substantial proportion of the total population (~ . billion people, %), and would make it difficult to understand global heterogeneity in the distribution of each target population. therefore, in this study, missing data were tackled by mice algorithm ( ) in which biases can be overcome and incomplete data are allowed to be included in analyses. unlike other approaches using values imputed from average numbers, however, mcie algorithm allows for the uncertainty about the missing values by creating several different plausible imputed datasets from their predictive distribution (based on the observed data). variability between the imputed datasets can be considered, and average estimates can be obtained ( ) . this gives more robust estimates of the size of target populations on local, regional, and global scales. a few limitations should be highlighted in this study. lack of timely data for constrains estimates of population sizes in many countries. however, the distribution of target occupational and high-risk groups is likely stable over a few years. second, we could not explore within-country variations in target populations. actual vaccine allocation plans should be carefully investigated in relation to the policy decisions of each population when relevant data are available in a given country. third, due to data availability, we cannot provide estimates for the size of target population by other demographic factors, such as racial and ethnic groups which are reported to be risk factors for covid- risk and adverse outcomes ( , ) . in addition, given relatively lower prevalence of underlying conditions among essential workers aged < years of age ( . %, all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint %ci . - . %) ( ), we did not subtract these essential workers with underlying conditions from the broader group of adults with underlying conditions. in conclusion, findings from this study provide evidence base for global, regional, and national vaccine prioritization and allocation plan. within and betweenregion variations in the size of target populations emphasize the tenuous balance between vaccine demand and supply, especially in low-and middle-income countries without sufficient capacity to meet domestic demand for covid- vaccine. moreover, in a given country, vaccine prioritization and allocation should be targeted towards on the basis of specific health or societal objectives, and local variations at the individual or regional levels. w. wang, q. wu, and h. yu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. c. viboud, m. ajelli, and h. yu were responsible for its conception and design. w. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in wang, q. wu, x. chen, and x. bai did the data analysis. j. yang, c. viboud and m. ajelli provided administrative, technical, or material support. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in draft landscape of covid- candidate vaccines - seroprevalence estimates of sars-cov- infection in convenience sample -oregon prevalence of sars-cov- in spain (ene-covid): a nationwide, population-based seroepidemiological study seroprevalence of anti-sars-cov- igg antibodies in serocov-pop): a population-based study serological evidence of human infection with sars-cov- : a systematic review and meta-analysis. medrxiv emerging manufacturers engagements in the covid − vaccine research, development and supply an ethical framework for global vaccine allocation world health organization, the access to covid- tools (act) interim framework for covid- vaccine allocation and distribution in the united states joint committee on vaccination and immunisation: interim advice on priority groups for covid- vaccination a global framework to ensure equitable and fair allocation of covid- products and potential implications for covid- vaccines the plight of essential workers during the covid- pandemic global, regional, and national estimates of the population at increased risk of severe covid- due to underlying health conditions in all rights reserved. no reuse allowed without permission preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted doi: medrxiv preprint : a modelling study changes in contact patterns shape the dynamics of the covid- outbreak in china multivariate imputation by chained equations in r determinants of covid- vaccine acceptance in the us world health organization, united nations children's fund vaccination and herd immunity to infectious diseases clinical relevance of age-related immune dysfunction multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls is ethnicity linked to incidence or outcomes of covid- ? factors associated with covid- -related death using opensafely prevalence of underlying medical conditions among selected essential critical infrastructure workers -behavioral risk factor surveillance system all rights reserved. no reuse allowed without permission. perpetuity preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted the study was funded by the national science all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in key: cord- -ikepr p authors: tulchinsky, theodore h.; varavikova, elena a. title: expanding the concept of public health date: - - journal: the new public health doi: . /b - - - - . - sha: doc_id: cord_uid: ikepr p ancient societies recognized the needs of sanitation, food safety, workers’ health, and medical care to protect against disease and to promote well-being and civic prosperity. new energies and knowledge since the eighteenth century produced landmark discoveries such as prevention of scurvy and vaccination against smallpox. the biological germ theory and competing miasma theory each proved effective in sanitation, and immunization in control of infectious diseases. non-communicable diseases as the leading causes of mortality have responded to innovative preventive care of health risk factors, smoking, hypertension, obesity, physical inactivity, unhealthful diets, and diabetes mellitus. health promotion proved effective to modern public health in tackling disease origins, individual behavior, and social and economic conditions. the global burden of infectious and non-communicable diseases, aging and chronic illness faces rising costs and still inadequate prevention. the evolution of concepts of public health will have to address these new challenges of population health. the development of public health from its ancient and recent roots, especially in the past several centuries, is a continuing process, with evolutionary and sometimes dramatic leaps forward, and important continuing and new challenges for personal and population health and well-being. everything in the new public health is about preventing avoidable disease, injuries, disabilities, and death while promoting and maximizing a healthy environment and optimal conditions for current and future generations. thus, the new public health addresses overall health policy, resource allocation, as well as the organization, management, and provision of medical care and of health systems in general within a framework of overall social policy and in a community, state, national, transnational, and global context. the study of history (see chapter ) helps us to understand the process of change, to define where we came from and where we are going. it is vital to recognize and understand change in order to deal with radical transformations in direction that occur as a result of changing demography and epidemiology, new science, evolving best practices in public health and clinical medicine, and above all inequalities in health resulting from societal system failures and social and economic factors. health needs will continue to develop in the context of environmental, demographic and societal adjustments, with knowledge gained from social and physical sciences, practice, and economics. for the coming generations, this is about not only the quality of life, but the survival of society itself. over the past century there have been many definitions of public health and health for all. mostly they represent visions and ideals of societal and global aspirations. this chapter examines the very base of the new public health, which encompasses the classic issues of public health with recognition of the advances made in health promotion and the management of health care systems as integral components of societal efforts to improve the health of populations and of individuals. what follows in succeeding chapters will address the major concepts leading to modern and comprehensive elements of public health. inevitably, concepts of public health continue to evolve and to develop both as a philosophy and as a structured discipline. as a professional field, public health requires specialists trained with knowledge and appreciation of its evolution, scientific advances, concepts, and best practices, old and modern. it demands sophisticated professional and managerial skills, the ability to address a problem, reasoning to define the issues, and to advocate, initiate, develop, and implement new and revised programs. it calls for profoundly humanistic values and a sense of responsibility towards protecting and improving the health of communities and every individual. in the twenty-first century, this set of values was well expressed in the human development index agreed to by nations (box . ). public health is a multidimensional field and therefore multidisciplinary in its workforce and organizational needs. it is based on scientific advances and application of best practices as they evolve, and includes many concepts, including holistic health, first established in ancient times. the discussion will return to the diversity of public health throughout this chapter and book many times. in previous centuries, public health was seen primarily as a discipline which studies and implements measures for control of communicable diseases, primarily by sanitation and vaccination. the sanitary revolution, which preceded the development of modern bacteriology, made an enormous contribution to improved health, but many other societal factors including improved nutrition, education, and housing were no less important for population health. maternal and child health, occupational health, and many other aspects of a growing public health network of activities played important roles, as have the physical and social environment and personal habits of living in determining health status. in recent decades recognition of the importance of women's health and health inequalities associated with many high-risk groups in the population have seen both successes and failures in addressing their challenges. male health issues have received less attention, apart from issues associated with specific diseases, or those of healthy military personnel. the scope of public health has changed along with growth of the medical, social, and public health sciences, public expectations, and practical experience. taken together, these have all contributed to changes in the concepts and causes of disease. health systems that fail to adjust to changes in fundamental concepts of public health suffer from immense inequity and burdens of preventable disease, disability, and death. this chapter examines expanding concepts of public health, leading to the development of a new public health. public health has evolved as a multidisciplinary field that includes the use of basic and applied science, education, social sciences, economics, management, and communication skills to promote the welfare of the individual and the community. it is greater than the sum of its component elements and includes the art and politics of the funding and coordination of the wide diversity of community and individual health services. the concept of the interdependence of health in body and in mind has ancient origins. they continue to be fundamental to individuals and societies, and part of the fundamental rights of all humans to have knowledge of healthful lifestyles and to have access to those measures of good health that society alone is able to provide, such as immunization programs, food and drug safety and quality standards, environmental and occupational health, and universal access to high-quality primary and specialty medical and other vital health services. this holistic view of balance and equilibrium may be a renaissance of classical greek and biblical traditions, applied with the broad new knowledge and experience of public health and medical care of the nineteenth, twentieth, and the early years of the twenty-first centuries as change continues to challenge our capacity to adapt. the competing nineteenth-century germ and miasma theories of biological and environmental causation of illness each contributed to the development of sanitation, hygiene, immunization, and understanding of the biological and social determinants of disease and health. they come together in the twenty-first century encompassed in a holistic new public health addressing individual and population health needs. medicine and public health professionals both engage in organization and in direct care services. these all necessitate an understanding of the issues that are included in the new public health, how they evolved, interact, are put together in organizations, and are financed and operated in various parts of the world in order to understand changes going on before our eyes. great success has been achieved in reducing the burden of disease with tools and concepts currently at our disposal. the idea that this is an entitlement for everyone was articulated in the health for all concept of alma-ata in . the health promotion movement emerged in the s and showed dramatically effective results in managing the new human immunodeficiency virus (hiv) pandemic and in tackling smoking and other risk factors for non-communicable diseases (ncds). a health in all policy concept emerged in promoting the concept that health should be a basic component of all public and private policies to achieve the full potential of public health and eliminate inequalities associated with social and economic conditions. profound changes are taking place in the world population, and public health is crucial to respond accordingly: mass migration to the cities, fewer children, extended life expectancy, and the increase in the population of older people who are subject to more chronic diseases and disabilities in a changing physical, social, and economic climate. health systems are challenged with continuing development of new medical technologies and related reforms in clinical practice, while experiencing strong influences of pharmaceuticals and the medicalization of health, with prevention and health promotion less central in priorities and resource allocation. globalization of health has many meanings: international trade, improving global communications, and economic changes with increasing flows of goods, services, and people. ecological and climate change bring droughts, hurricanes, arctic meltdown, and rising sea levels. globalization also has political effects, with water and food shortages, terrorism, and economic distress affecting billions of people. in terms of health, disease can spread from one part of the world to others, as in pandemics or in a quiet spread such as that of west nile fever moving from its original middle eastern natural habitat to the americas and europe, or severe acute respiratory syndrome (sars), which spread with lightning speed from chinese villages to metropolitan cities such as toronto, canada. it can also mean that the ncds characteristic of the industrialized countries are now recognized as the leading causes of death in low-and middle-income countries, associated with diet, activity levels, and smoking, which are themselves pandemic risk factors. the potential for global action in health can also be dramatic. the eradication of smallpox was a stunning victory for public health. the campaign to eradicate poliomyelitis is succeeding even though the end-stage is fraught with setbacks, and measles elimination has turned out to be more of a challenge than was anticipated a decade ago, with resurgence in countries thought to have it under control. global health policies have also made the achievements of public-private partnerships of great importance, particularly in vaccination and acquired immunodeficiency syndrome (aids) control programs. there have been failures as well, with very limited progress in human resources development of the public health workforce in low-income countries. the new public health is necessarily comprehensive in scope and it will continue to evolve as new technologies and scientific discoveries -biological, genetic, and sociological -reveal more methods of disease control and health promotion. it relates to or encompasses all community and individual activities directed towards improving the environment for health, reducing factors that contribute to the burden of disease, and fostering those factors that relate directly to improved health. its programs range broadly from immunization, health promotion, and child care, to food labeling and fortification, as well as to the assurance of well-managed, accessible health care services. a strong public health system should have adequate preparedness for natural and human-made disasters, as seen in the recent tsunamis, hurricanes, biological or other attacks by terrorists, wars, conflicts, and genocidal terrorism (box . ) . the concepts of health promotion and disease prevention are essential and fundamental elements of the new public health. parallel scientific advances in molecular biology, genetics and pharmacogenomics, imaging, information technology, computerization, biotechnology, and nanotechnology hold great promise for improving the productivity of the health care system. advances in technology with more effective and less expensive drug and vaccine development, with improved safety and effectiveness, and fewer adverse reactions, will over time greatly increase efficiency in prevention and treatment modalities. the new public health is important as a conceptual base for training and practice of public health. it links classical topics of public health with adaptation in the organization and financing of personal health services. it involves a changed paradigm of public health to incorporate new advances in political, economic, and social sciences. failure at the political level to appreciate the role of public health in disease control holds back many societies in economic and social development. at the same time, organized public health systems need to work to reduce inequities between and inside countries to ensure equal access to care. it also demands special attention through health promotion activities of all kinds at national and local societal levels to provide access for groups with special risks and needs to medical and community health care with the currently available and newly developing knowledge and technologies. the great gap between available capabilities to prevent and treat disease and actually reaching all in need is still the the mission of the nph is to maximize human health and well-being for individuals and communities, nationally and globally. the methods with which the nph works to achieve this are in keeping with recognized international best practices and scientific advances: . societal commitment and sustained efforts to maximize quality of life and health, economic growth with equity for all (health for all and health in all). collaboration between international, national, state, and local health authorities working with public and private sectors to promote health awareness and activities essential for population health. . health promotion of knowledge, attitudes, and practices, including legislation and regulation to protect, maintain, and advance individual and community health. . universal access to services for prevention and treatment of illness and disability, and promotion of maximum rehabilitation. . environmental, biological, occupational, social, and economic factors that endanger health and human life, addressing: (a) physical and mental illness, diseases and infirmity, trauma and injuries (b) local and global sanitation and environmental ecology (c) healthful nutrition and food security including availability, quality, safety, access, and affordability of food products (d) disasters, natural and human-made, including war, terrorism, and genocide (e) population groups at special risk and with specific health needs. . promoting links between health protection and personal health services through health policies and health systems management, recognizing economic and quality standards of medical, hospital, and other professional care in health of individuals and populations. . training of professional public health workforces and education of all health workers in the principles of ethical best practices of public health and health systems. . research and promotion of current best practices: wide application of current international best practices and standards. . mobilizing the best available evidence from local and international scientific and epidemiological studies and best practices recognized as contributing to the overall goal. . maintaining and promoting equity for individual and community rights to health with high professional and ethical standards. source of great international and internal national inequities. these inequities exist not only between developed and developing countries, but also within transition countries, mid-level developing countries, and those newly emerging with rapid economic development. the historical experience of public health will help to develop the applications of existing and new knowledge and societal commitment to social solidarity in implementation of the new discoveries for every member of the society, despite socioeconomic, ethnic, or other differences. political will and leadership in health, adequate financing, and organization systems in the health setting are crucial to furthering health as an objective with defined targets, supported by well-trained staff for planning, management, and monitoring the population health and functioning of health systems. political leadership and professional support are both indispensable in a world of limited resources, with high public expectations and the growing possibilities of effectiveness of public health programs. well-developed information and knowledge management systems are required to provide the feedback and information needed for good management. it includes responsibilities and coordination at all levels of government. non-governmental organizations (ngos) and participation of a well-informed media and strong professional and consumer organizations also have significant roles in furthering population health. no less important are clear designations of responsibilities of the individual for his or her own health, and of the provider of care for humane, high-quality professional care. the complexities and interacting factors are suggested in figure . , with the classic host-agent-environment triad. many changes have signaled a need for transformation towards the new public health. religion, although still a major political and policy-making force in many countries, is no longer the central organizing power in most societies. organized societies have evolved from large extended families and tribes to rural societies, cities, regions, and national governments. with the growth of industrialized urban communities, rapid transport, and extensive trade and commerce in multinational economic systems, the health of individuals and communities has become more than just a personal, family, and/or local problem. an individual is not only a citizen of the village, city, or country in which he or she lives, but a citizen of a "global village". the agricultural revolutions and international explorations of the fifteenth to seventeenth centuries that increased food supply and diversity were followed only much later by knowledge of nutrition as a public health issue. the scientific revolution of the seventeenth to nineteenth centuries provided the basics to describe and analyze the spread of disease and the poisonous effects of the industrial revolution, including crowded living conditions and pollution of the environment with serious ecological damage. in the latter part of the twentieth century, a new agricultural "green revolution" had a great impact in reducing human deprivation internationally, yet the full benefits of healthier societies are yet to be realized in the large populations living in abject poverty in sub-saharan africa, south-east asia, and other parts of the world. global water shortages can be addressed with new methods of irrigation, water conservation and the application of genetic sciences to food production, and issues of economics and food security are of great importance to a still growing world population with limited supplies. further, food production capacity can and must be enlarged to meet current food insecurity, rising expectations of developing nations, and population growth. the sciences of agriculture-related fields, including genetic sciences and practical technology, will be vital to human progress in the coming decades. these and other societal changes discussed in chapter have enabled public health to expand its potential and horizons, while developing its pragmatic and scientific base. organized public health in the twentieth century proved effective in reducing the burden of infectious diseases and has contributed to improved quality of life and longevity by many years. in the last half-century, chronic diseases have become the primary causes of morbidity and mortality in the developed countries and increasingly in developing countries. growing scientific and epidemiological knowledge increases the capacity to deal with these diseases. many aspects of public health can only be influenced by the behavior of and risks to the health of individuals. these require interventions that are more complex and relate to societal, environmental, and community standards and expectations as much as to personal lifestyle. the dividing line between communicable and non-communicable diseases changes over time. scientific advances have shown the causation of chronic conditions by infectious agents and their prevention by curing the infection, as in helicobacter pylori and peptic ulcers, and in prevention of cancer of the liver and cervix by immunization for hepatitis b and human papillomavirus (hpv), respectively. chronic diseases have come to the center stage in the "epidemiological transition", as infectious diseases came under increasing control. this, in part, has created a need for reform in the funding and management of health systems due to rapidly rising costs, aging of the population, the rise of obesity and diabetes and other chronic conditions, mushrooming therapeutic technology, and expanding capacity to deal with public health emergencies. reform is also needed in international assistance to help less developed nations build the essential infrastructure to sustain public health in the struggle to combat aids, malaria, tuberculosis (tb), and the major causes of preventable infant, childhood, and motherhood-related deaths. the nearly universal recognition of the rights of people to have access to health care of acceptable quality by international standards is a challenge of political will and leadership backed up by adequate staffing with public health-trained staff and organizations. the challenges of the current global economic crisis are impacting social and health systems around the world. the interconnectedness of managing health systems is part of the new public health. setting the priorities and allocating resources to address these challenges requires public health training and orientation of the professionals and institutions participating in the policy, management, and economics of health systems. conversely, those who manage such institutions are recognizing the need for a wide background in public health training in order to fulfill their responsibilities effectively. concepts such as objectives, targets, priorities, cost-effectiveness, and evaluation have become part of the new public health agenda. an understanding of how these concepts evolved will help the future health provider or manager to cope with the complexities of mixing science, humanity, and effective management of resources to achieve higher standards of health, and to cope with new issues as they develop in the broad scope of the new public health for the twenty-first century, in what breslow called the "third public health era" of long and healthy quality of life (box . ). health can be defined from many perspectives, ranging from statistics on mortality, life expectancy, and morbidity rates to idealized versions of human and societal perfection, as in the world health organization's (who's) founding charter. the first public health era -the control of communicable diseases. second public health era -the rise and fall of chronic diseases. third public health era -the development of long and high-quality life. preamble to the constitution of the who, as adopted by the international health conference in new york in and signed by the representatives of states, entered into force on april , with the widely cited definition: "health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity". this definition is still important conceptually as an ideal accepted as fundamental to public policy over the years. a more operational definition of health is a state of equilibrium of the person with the biological, physical, and social environment, with the object of maximum functional capability. health is thus seen as a state characterized by anatomical, physiological, and psychological integrity, and an optimal functional capability in the family, work, and societal roles (including coping with associated stresses), a feeling of well-being, and freedom from risk of disease and premature death. deviances in health are referred to as unhealthy and constitute a disease nomenclature. there are many interrelated factors in disease and in their management through what is now called risk reduction. in , claude bernard described the phenomenon of adaptation and adjustment of the internal milieu of the living organism to physiological processes. this concept is fundamental to medicine. it is also central to public health because understanding the spectrum of events and factors between health and disease is basic to the identification of contributory factors affecting the balance towards health, and to seeking the points of potential intervention to reverse the imbalance. as described in chapter , from the time of hippocrates and galen, diseases were thought to be due to humors and miasma or emanations from the environment. this was termed the miasma theory, and while without a direct scientific explanation, it was acted upon in the early to mid-nineteenth century and promoted by leading public health theorists including florence nightingale, with practical and successful measures to improve sanitation, housing, and social conditions, and having important results in improving health conditions. the competing germ theory developed by pioneering nineteenthcentury epidemiologists (panum, snow, and budd), scientists (pasteur, cohn, and koch), and practitioners (lister and semmelweiss) led to the science of bacteriology and a revolution in practical public health measures. the combined application of the germ (agent-host-environment) and miasma theories (social and sanitary environment) has been the basis of classic public health, with enormous benefits in the control of infectious and other diseases or harmful conditions. the revolutionary changes occurring since the s have brought about a decline in cardiovascular and cancer mortality, and conceptual changes such as health for all and health in all to bring health issues to all policies at both governmental and individual levels. the concepts of public health advanced with the marc lalonde health field concept (new perspectives on the health of canadians, ) , stating that health was the result of the physical and social environment, lifestyle and personal habits, genetics, as well as organization and provision of medical care. the lalonde report was a key concept leading to ideas advanced at the alma-ata conference on primary care held in and more explicitly in the development of the basis for health promotion as articulated in the ottawa charter of on health promotion. this marked the beginning of a whole new aspect of public health, which proved itself in addressing with considerable success the epidemic of hiv and cardiovascular diseases. in the usa, the surgeon general's reports of on smoking and health, and of defining health targets as national policy promoted the incorporation of "management by objectives" from the business world applied to the health sector (see chapter ). this led to healthy people usa and later versions, and the united nations (un) millennium development goals (mdgs), aimed primarily at the middle-and low-income countries (box . ). the identification of infectious causes of cancers of the liver and cervix established a new paradigm in epidemiology, and genetic epidemiology has important potential for public health and clinical medicine. in the basic host-agent-environment paradigm, a harmful agent comes through a sympathetic environment into contact with a susceptible host, causing a specific disease. this idea dominated public health thinking until the midtwentieth century. the host is the person who has or is at risk for a specific disease. the agent is the organism or direct cause of the disease. the environment includes the external factors which influence the host, his or her susceptibility to the agent, and the vector which transmits or carries the agent to the host from the environment. this explains the causation and transmission of many diseases. this paradigm (figure . ), in effect, joins together the contagion and miasma theories of disease causation. a specific agent, a method of transmission, and a susceptible host are involved in an interaction, which are central to the infectivity or severity of the disease. the environment can provide the carrier or vector of an infective (or toxic) agent, and it also contributes factors to host susceptibility; for example, unemployment, poverty, or low education level. the expanded host-agent-environment paradigm widens the definition of each of the three components ( figure . ), in relation to both acute infectious and chronic noninfectious disease epidemiology. in the latter half of the twentieth century, this expanded host-agent-environment paradigm took on added importance in dealing with the complex of factors related to chronic diseases, now the leading causes of disease and premature mortality in the developed world, and increasingly in developing countries. interventions to change host, environmental, or agent factors are the essence of public health. in infectious disease control, the biological agent may be removed by pasteurization of food products or filtration and disinfection (chlorination) of water supplies to prevent transmission of waterborne disease. the host may be altered by immunization to provide immunity to a specific infective organism. the environment may be changed to prevent transmission by destroying the vector or its reservoir of the disease. a combination of these interventions can be used against a specific risk factor, toxic or nutritional deficiency, infectious organism, or disease process. vaccine-preventable diseases may require both routine and special activities to boost herd immunity to protect the individual and the community. for other infectious diseases for which there is no vaccine (e.g., malaria), control involves a broad range of activities including case finding and treatment to improve the individual's health and to reduce the reservoir of the disease in the population, and other measures such as bed nets to reduce exposure of the host to vector mosquitoes, as well as vector control to reduce the mosquito population. tb control requires not only case finding and treatment, but understanding the contributory factors of social conditions, diseases with tb as a secondary condition (substance abuse and aids), agent resistance to treatment, and the inability of patients or carriers to complete treatment without supervision. sexually transmitted infections (stis) which are not controllable by vaccines require a combination of personal behavior change, health education, medical care, and skilled epidemiology. with non-infectious diseases, intervention is even more complex, involving human behavior factors and a wide range of legal, administrative, and educational issues. there may be multiple risk factors, which have a compounding effect in disease causation, and they may be harder to alter than infectious diseases factors. for example, smoking in and of itself is a risk factor for lung cancer, but exposure to asbestos fibers has a compounding effect. preventing exposure to the compounding variables may be easier than smoking cessation. reducing trauma morbidity and mortality is equally problematic. the identification of a single specific cause of a disease is of great scientific and practical value in modern public health, enabling such direct interventions as the use of vaccines or antibiotics to protect or treat individuals from infection by a causative organism, toxin, deficiency condition, or social factor. the cumulative effects of several contributing or risk factors in disease causation are also of great significance in many disease processes, in relation to infectious diseases such as nutritional status as for chronic diseases such as the cardiovascular group. the health of an individual is affected by risk factors intrinsic to that person as well as by external factors. intrinsic factors include the biological ones that the individual inherits and those life habits he or she acquires, such as smoking, overeating, or engaging in other high-risk behaviors. external factors affecting individual health include the environment, the socioeconomic and psychological state of the person, the family, and the society in which he or she lives. education, culture, and religion are also contributory factors to individual and community health. there are factors that relate to health of the individual in which the society or the community can play a direct role. one of these is provision of medical care. another is to ensure that the environment and community services include safety factors that reduce the chance of injury and disease, or include protective measures; for example, fluoridation of a community water supply to improve dental health, and seat-belt or helmet laws to reduce motor vehicle injury and death. these modifying factors may affect the response of the individual or the spread of an epidemic (see chapter ). an epidemic may also include chronic disease, because common risk factors may cause an excess of cases in a susceptible population group, in comparison to the situation before the risk factor appeared, or in comparison to a group not exposed to the risk factor. these include rapid changes or "epidemics" in such conditions as type diabetes, asthma, cardiovascular diseases, trauma, and other non-infectious disorders. disease is a dynamic process, not only of causation, but also of incubation or gradual development, severity, and the effects of interventions intended to modify outcome. knowledge of the natural history of disease is fundamental to understanding where and with what means intervention can have the greatest chance for successful interruption or change in the disease process for the patient, family, or community. the natural history of a disease is the course of that disease from beginning to end. this includes the factors that relate to its initiation; its clinical course leading up to resolution, cure, continuation, or long-term sequelae (further stages or complications of a disease); and environmental or intrinsic (genetic or lifestyle) factors and their effects at all stages of the disease. the effects of intervention at any stage of the disease are part of the disease process (figure . ). as discussed above, disease occurs in an individual when agent, host, and environment interact to create adverse conditions of health. the agent may be an infectious organism, a chemical exposure, a genetic defect, or a deficiency condition. a form of individual or social behavior, such as reckless driving or risky sexual behavior, may lead to injury or disease. the host may be immune or susceptible as a result of many contributing social and environmental factors. the environment includes the vector, which may be a malaria-bearing mosquito, a contaminated needle shared by drug users, lead-contaminated paint, or an abusive family situation. assuming a natural state of "wellness" -i.e., optimal health or a sense of well-being, function, and absence of disease -a disease process may begin with the onset of a disease, infectious or non-infectious, following a somewhat characteristic pattern of "incubation" described by clinicians and epidemiologists. preclinical or predisposing events may be detected by a clinical history, with determination of risk including possible exposure or presence of other risk factors. interventions, before and during the process, are intended to affect the later course of the disease. the clinical course of a disease, or its laboratory or radiological findings, may be altered by medical or public health intervention, leading to the resolution or continuation of the disease with fewer or less severe secondary sequelae. thus, the intervention becomes part of the natural history of the disease. the natural history of an infectious disease in a population will be affected by the extent of prior vaccination or previous exposure in the community. diseases particular to children are often so because the adult population is immune from previous exposure or vaccinations. measles and diphtheria, primarily childhood diseases, now affect adults to a large extent because they are less protected by naturally acquired immunity or are vulnerable when their immunity wanes naturally or as a result of inadequate vaccination in childhood. in chronic disease management, high costs to the patient and the health system accrue where preventive services or management are inadequate, not yet available, or inaccessible or where there is a failure to apply the necessary interventions. the progress of diabetes to severe complications such as cardiovascular, renal, and ocular disease is delayed or reduced by good management of the condition, with a combination of smoking cessation, diet, exercise, and medications with good medical supervision. the patient with advanced chronic obstructive pulmonary disease or congestive heart failure may be managed well and remain stable with smoking avoidance, careful management of medications, immunizations against influenza and pneumonia, and other prevention-oriented care needs. where these are not applied or if they fail, the patient may require long and expensive medical and hospital care. failure to provide adequate supportive care will show up in ways that are more costly to the health system and will prove more life-threatening to the patient. the goal is to avoid where possible the necessity for tertiary care, substituting tertiary prevention, i.e., supportive rehabilitation to maximum personal function and maintaining a stable functional status. as in an individual, the phenomenon of a disease in a population may follow a course in which many factors interplay, and where interventions affect the natural course of the disease. the epidemiological patterns of an infectious disease can be assessed in their occurrence in the population or their mortality rates, just as they can for individual cases. the classic mid-nineteenth-century description of measles in the faroe islands by panum showed the transmission and the epidemic nature of the disease as well as the protective effect of acquired immunity (see chapter ). similar, more recent breakthroughs in medical, epidemiological, biological, and social sciences have produced enormous benefit for humankind as discussed throughout this text, with some examples. these include the eradication of smallpox and in the coming years, poliomyelitis, measles, leprosy, and other dreaded diseases known for millennia; the near-elimination of rheumatic heart disease and peptic ulcers in the industrialized countries; vast reduction in mortality from stroke and coronary heart disease (chd); and vaccines (against hepatitis b and hpv) for the prevention of cancers. these and other great achievements of the twentieth and early part of the twenty-first centuries hold great promise for humankind in the coming decades, but great challenges lie ahead as well. the biggest challenge is to bring the benefits of known public health capacity to the poorest population of each country and the poorest populations globally. in developed countries a major challenge is to renew efforts of public health capacity to bear on prevention of chronic conditions such as diabetes and obesity, considered to be at pandemic proportions; and the individual and societal effects of mental diseases. in public health today, fears of a pandemic of avian influenza are based on transmission of avian or other animal-borne (zoonotic) prions or viruses to humans and then their adaptation permitting human-to-human spread. with large numbers of people living in close contact with many animals (wild and domestic fowl), such as in china and south-east asia, and rapid transportation around the world, the potential for global spread of disease is almost without historical precedent. indeed, many human infectious diseases are zoonotic in origin and transferred from natural wildlife reservoirs to humans either directly or via domestic or other wild animals, such as from birds to chickens to humans in avian influenza. monitoring or immunization of domestic animals requires a combination of multidisciplinary zoonotic disease management strategies, public education and awareness, and veterinary public health monitoring and control. rift valley fever, equine encephalitis, and more recently sars and avian influenza associated with bird-borne viral disease which can affect humans, each show the terrible dangers of pandemic diseases. ebola virus is probably sustained between outbreaks among fruit bats, or as recently suggested wild or domestic pigs, and may become a major threat to public health as human case fatality rates decline, meaning that patients and carriers, or genetic drift of the virus with possible airborne transmission, may spread this deadly disease more widely than in the past (see chapter ). the health of populations, like the health of individuals, depends on societal factors no less than on genetics, personal risk factors, and medical services. social inequalities in health have been understood and documented in public health over the centuries. the chadwick and shattuck reports of - documented the relationship of poverty and bad sanitation, housing, and working conditions with high mortality, and ushered in the idea of social epidemiology. political and social ideologies thought that the welfare state, including universal health care systems of one type or another, would eliminate social and geographic differences in health status and this is in large part true. from the introduction of compulsory health insurance in germany in the s to the failed attempt in the usa at national health insurance in (see chapters , and ) and the more recent achievements of us president obama in - , social reforms to deal with inequalities in health have focused on improving access to medical and hospital care. almost all industrialized countries have developed such systems, and the contribution of these programs to improve health status has been an important part of social progress, especially since world war ii. but even in societies with universal access to health care, people of lower socioeconomic status (ses) suffer higher rates of morbidity and mortality from a wide variety of diseases. the black report (douglas black) in the uk in the early s pointed out that the class v population (unskilled laborers) had twice the total and specific mortality rates of the class i population (professional and business) for virtually all disease categories, ranging from infant mortality to death from cancer. the report was shocking because all britons have had access to the comprehensive national health service (nhs) since its inception in , with access to a complete range of services at no cost at time of service, close relations to their general practitioners, and good access to specialty services. these findings initiated reappraisals of the social factors that had previously been regarded as the academic interests of medical sociologists and anthropologists and marginal to medical care. more recent studies and reviews of regional, ethnic, and socioeconomic differentials in patterns of health care access, morbidity, and mortality indicate that health inequities are present in all societies including the uk, the usa, and others, even with universal health insurance or services. the ottawa charter on health promotion in placed a new paradigm before the world health community that recognized social and political factors as no less important ion health that traditional medical and sanitary public health measures. these concepts helped the world health community to cope with new problems such as hiv/aidsfor which there was neither a medical cure nor a vaccine to prevent the disease. its control came to depend in the initial decades almost entirely on education and change in lifestyles, until the advent of the antiretroviral drugs in the s. there is still no viable vaccine. although the epidemiology of cardiovascular disease shows the direct relationship of the now classic risk factors of stress, smoking, poor diet, and physical inactivity, differences in mortality from cardiovascular disease between different classes among british civil servants are not entirely explainable by these factors. the differences are also affected by social and economic issues that may relate to the psychological needs of the individual, such as the degree of control people have over their own lives. blue-collar workers have less control over their lives, their working life in particular, than their white-collar counterparts, and have higher rates of chd mortality than higher social classes. other work shows the effects of migration, unemployment, drastic social and political change, and binge drinking, along with protective effects of healthy lifestyle, religiosity, and family support systems in cardiovascular diseases. social conditions affect disease distribution in all societies. in the usa and western europe, tb has re-emerged as a significant public health problem in urban areas partly because of high-risk population groups, owing to poverty and alienation from society, as in the cases of homelessness, drug abuse, and hiv infection. in countries of eastern europe and the former soviet union, the recent rise in tb incidence has resulted from various social and economic factors in the early s, including the large-scale release of prisoners. in both cases, diagnosis and prescription of medication are inadequate, and the community at large becomes at risk because of the development of antibioticresistant strains of tubercle bacillus readily spread by inadequately treated carriers, acting as human vectors. studies of ses and health are applicable and valuable in many settings. in alameda county, california, differences in mortality between black and white population groups in terms of survival from cancer became insignificant when controlled for social class. a -year follow-up study of the county population reported that low-income families in california are more likely than those on a higher income to have physical and mental problems that interfere with daily life, contributing to further impoverishment. studies of the association between indicators of ses and recent screening in the usa, australia, finland, and elsewhere showed that lower ses women use less preventive care such as papanicolaou (pap) smears for cervical cancer than women of higher ses, despite having greater risk for cervical cancer. many factors in ses inequalities are involved, including transportation and access to primary care, differences in health insurance coverage, educational levels, poverty, high-risk behaviors, social and emotional distress, feeling a lack of control over one's own life, employment, occupation, and inadequate family or community social support systems. many barriers exist owing to difficulties in access and the lack of availability of free or low-cost medical care, and the absence or limitations of health insurance is a further factor in the socioeconomic gradient. the recognition that health and disease are influenced by many factors, including social inequalities, plays a fundamental role in the new public health paradigm. health care systems need to take into account economic, social, physical, and psychological factors that otherwise will limit the effectiveness of even the best medical care. the health system includes access to competent and responsible primary care as well as by the wider health system, including health promotion, specific prevention and population-based health protection. the paradigm of the host-agent-environment triad (figures . and . ) is profoundly affected by the wider context. the sociopolitical environment and organized efforts at intervention affect the epidemiological and clinical course of disease of the individual. medical care is essential, as is public health, but the persistent health inequities seen in most regions and countries require societal attention. success or failure in improving the conditions of life for the poor, and other vulnerable "risk groups", affect national or regional health status and health system performance. the health system is meant to reduce the occurrence or bad outcome of disease, either directly by primary prevention or treatment as secondary prevention or by maximum rehabilitation as tertiary prevention, or equally important indirectly by reducing community or individual risk factors. the the effects of social conditions on health can be partly offset by interventions intended to promote healthful conditions; for example, improved sanitation, or through good-quality primary and secondary health services, used efficiently and effectively made available to all. the approaches to preventing disease or its complications may require physical changes in the environment, such as removal of the broad street pump handle to stop the cholera epidemic in london, or altering diets as in goldberger's work on pellagra. some of the great successes of public health have been and continue to be low technology. examples, among many others, include insecticide-impregnated bednets and other vector control measures, oral rehydration solutions, treatment and cure of peptic ulcers, exercise and diet to reduce obesity, hand washing in hospitals (and other health facilities), community health workers, and condoms and circumcision for the prevention of stis, including hiv and cancer of the cervix. the societal context in terms of employment, social security, female education, recreation, family income, cost of living, housing, and homelessness is relevant to the health status of a population. income distribution in a wealthy country may leave a wide gap between the upper and lower socioeconomic groups, which affects health status. the media have great power to sway public perception of health issues by choosing what to publish and the context in which to present information to society. modern media may influence an individual's tendency to overestimate the risk of some health issues while underestimating the risk of others, ultimately influencing health choices, such as occurred with public concern regarding false claims of an association between the measles-mumps-rubella (mmr) vaccine and autism in the uk (see the wakefield effect, chapter ). the new public health has an intrinsic responsibility for advocacy of improved societal conditions in its mission to promote optimal community health. an ultimate goal of public health is to improve health and to prevent widespread disease occurrence in the population and in an individual. the methods of achieving this are wide and varied. when an objective has been defined in "social justice is a matter of life and death. it affects the way people live, their consequent chance of illness, and their risk of premature death. we watch in wonder as life expectancy and good health continue to increase in parts of the world and in alarm as they fail to improve in others. a girl born today can expect to live for more than years if she is born in some countries -but less than years if she is born in others. within countries there are dramatic differences in health that are closely linked with degrees of social disadvantage. differences of this magnitude, within and between countries, simply should never happen. these inequities in health, avoidable health inequalities arise because of the circumstances in which people grow, live, work, and age, and the systems put in place to deal with illness. the conditions in which people live and die are, in turn, shaped by political, social, and economic forces. social and economic policies have a determining impact on whether a child can grow and develop to its full potential and live a flourishing life, or whether its life will be blighted. increasingly the nature of the health problems rich and poor countries have to solve are converging. the development of a society, rich or poor, can be judged by the quality of its population's health, how fairly health is distributed across the social spectrum, and the degree of protection provided from disadvantage as a result of ill-health." preventing disease, the next step is to identify suitable and feasible methods of achieving it, or a strategy with tactical objectives. this determines the method of operation, course of action, and resources needed to carry it out. the methods of public health are categorized as health promotion, and primary, secondary, and tertiary prevention (box . ). health promotion is the process of enabling people and communities to increase control over factors that influence their health, and thereby to improve their health (adapted from the ottawa charter of health promotion, ; box . ). health promotion is a guiding concept involving activities intended to enhance individual and community health and well-being (box . ). it seeks to increase involvement and control by the individual and the community in their own health. it acts to improve health and social welfare, and to reduce specific determinants of diseases and risk factors that adversely affect the health, well-being, and productive capacities of an individual or society, setting targets based on the size of the problem but also the feasibility of successful intervention, in a cost-effective way. this can be through direct contact with the patient or risk group, or act indirectly through changes in the environment, legislation, or public policy. control of aids relies on an array of interventions that promote change in sexual behavior and other contributory risks such as sharing of needles among drug users, screening of blood supply, safe hygienic practices in health care settings, and education of groups at risk such as teenagers, sex workers, migrant workers, and many others. control of aids is also a clinical problem in that patients need antiretroviral therapy (art), but this becomes a management and policy issue for making these drugs available and at an affordable price for the poor countries most affected. this is an example of the challenge and effectiveness of health promotion and the new public health. health promotion is a key element of the new public health and is applicable in the community, the clinic or hospital, and in all other service settings. some health promotion activities are government legislative and box . modes of prevention l health promotion -fostering national, community, and individual knowledge, attitudes, practices, policies, and standards conducive to good health; promoting legislative, social, or environmental conditions; promoting knowledge and practices for self-care that reduce individual and community risk; and creating a healthful environment. it is directed toward action on the determinants of health. l health protection -activities of official health departments or other agencies empowered to supervise and regulate food hygiene, community and recreational water safety, environmental sanitation, occupational health, drug safety, road safety, emergency preparedness, and many other activities to eliminate or reduce as much as possible risks of adverse consequences to health. l primary prevention -preventing a disease from occurring, e.g., vaccination to prevent infectious diseases, advice to stop smoking to prevent lung cancer. l secondary prevention -making an early diagnosis and giving prompt and effective treatment to stop progress or shorten the duration and prevent complications from an already existing disease process, e.g., screening for hypertension or cancer of cervix and colorectal cancer for early case finding, early care and better outcomes. l tertiary prevention -stopping progress of an already occurring disease, and preventing complications, e.g., in managing diabetes and hypertension to prevent complications; restoring and maintaining optimal function once the disease process has stabilized, e.g., promoting functional rehabilitation after stroke and myocardial infarction with long-term follow-up care. health promotion (hp) is the process of enabling people to increase control over, and to improve their health. hp represents a comprehensive social and political process, and not only embraces actions directed at strengthening the skills and capabilities of individuals. hp also undertakes action directed towards changing social, environmental, and economic conditions so as to alleviate their impact on public and individual health. health promotion is the process of enabling people to increase control over the determinants of health and thereby improve their health. participation is essential to sustain health promotion action. the ottawa charter identifies three basic strategies for health promotion. these are advocacy for health to create the essential conditions for health indicated above; enabling all people to achieve their full health potential; and mediating between the different interests in society in the pursuit of health. these strategies are supported by five priority action areas as outlined in the ottawa charter for health promotion: regulatory interventions such as mandating the use of seat belts in cars, requiring that children be immunized to attend school, declaring that certain basic foods must have essential minerals and vitamins added to prevent nutritional deficiency disorders in vulnerable population groups, and mandating that all newborns should be given prophylactic vitamin k to prevent hemorrhagic disease of the newborn. setting food and drug standards and raising taxes on cigarettes and alcohol to reduce their consumption are also part of health promotion. promoting a healthy lifestyle is a major known obesity-preventive activity. health promotion is provided by organizations and people with varied professional backgrounds working towards common goals of improvement in the health and quality of individual and community life. initiatives may come from government with dedicated allocation of funds to address specific health issues, from donors, or from advocacy or community groups or individuals to promote a specific or general cause in health. raising awareness to inform and motivate people about their own health and lifestyle factors that might put them at risk requires teaching young people about the dangers of sexually transmitted diseases, smoking, and alcohol abuse to reduce risks associated with their social behavior. it might include disseminating information on healthy nutrition; for example, the need for folic acid supplements for women of childbearing age and multiple vitamins for elderly, as well as the elements of a healthy diet, compliance with immunization recommendations, compliance with screening programs, and many others. community and peer group attitudes and standards affect individual behavior. health promotion endeavors to create a climate of knowledge, attitudes, beliefs, and practices that are associated with better health outcomes. international conferences following on from the ottawa charter were held in adelaide in , sundsvall in , jakarta in , mexico in , bangkok in , and nairobi in . the principles of health promotion have been reiterated and have influenced public policy regarding public health as well as the private sector. health promotion has a track record of proven success in numerous public health issues where a biomedical solution was not available. the hiv/aids pandemic from the s until the late s had no medical treatment and control measures relied on screening, education, lifestyle changes, and supportive care. health promotion brought forward multiple interventions, from condom use and distribution, to needle exchanges for intravenous drug users, to male circumcision in high-prevalence african countries. medical treatment was severely limited until art was developed. the success of art also depends on a strong element of health promotion in widening the access to treatment and the success of medications to reduce transmission, most remarkably in reducing maternal-fetal transmission (see chapter ). similarly, in the battle against cardiovascular diseases, health promotion was an instrumental factor in raising public awareness of the importance of management of hypertension and smoking reduction, dietary restraint, and physical exercise. the success of massive reductions in stroke and chd mortality is as much the result of health promotion as of improved medical care (see chapter ). the character of public health carries with it a "good cop, bad cop" dichotomy. the "good cop" is persuasive and educational trying to convince people to do the right thing in looking after their own health: diet, exercise, smoking cessation, and others. on the other side, the "bad cop" role is regulatory and punitive. public health has a serious responsibility and role in the enforcement of laws and regulation to protect the public health. some of these are restrictive box . elements of health promotion . address the population as a whole in health-related issues, in everyday life as well as people at risk for specific diseases. . direct action to risk factors or causes of illness or death. . undertake activist approach to seek out and remedy risk factors in the community that adversely affect health. . promote factors that contribute to a better condition of health of the population. . initiate actions against health hazards, including communication, education, legislation, fiscal measures, organizational change, community development, and spontaneous local activities. . involve public participation in defining problems and deciding on action. . advocate relevant environmental, health, and social policy. . encourage health professional participation in health education and health advocacy. . advocate for health based on human rights and solidarity. . invest in sustainable policies, actions, and infrastructure to address the determinants of health. . build capacity for policy development, leadership, health promotion practice, knowledge transfer and research, and health literacy. . regulate and legislate to ensure a high level of protection from harm and enable equal opportunity for health and well-being for all people. . partner and build alliances with public, private, nongovernmental, and international organizations and civil society to create sustainable actions. . make the promotion of health central to the global development agenda. of individual rights that may damage other people or are requirements based on strong evidence of benefits to population health. readily accepted are food and drug standards, such as pasteurization of milk, and iodization of salt; requirements to drive on the right-hand side of the road (except in some countries such as the uk), to wear seat belts and for motorcyclists to wear safety helmets; and not smoking in public places. enforcement of these and similar statutory or regulatory requirements is vital in a civil society to protect the public from health hazards and to protect people from harm and exploitation by unscrupulous manufacturers and marketing. cigarette advertising and sponsorship of sports events by tobacco companies are banned in most upper income countries. the use of transfats in food manufacturing and baking is now banned and salt reduction is being promoted and even mandated in many us local authorities to reduce cardiovascular disease. advertising of unhealthy snack foods on children's television programs and during child-watching hours is commonly restricted. banning high-sugar soda drink distribution in schools is a successful intervention to reduce the current child obesity epidemic. melamine use in milk powders and baby formulas, which caused widespread illness and death of infants in china, is now banned and a punishable offence for manufacture or distribution in china and worldwide. examples of this aspect of public health are mentioned throughout this text, especially in chapters and on nutrition, and environmental and occupational health, respectively. the regulatory enforcement function of public health is sometimes controversial and portrayed as interference with individual liberty. fluoridation of community water supplies is an example where aggressive lobby groups opposing this safe and effective public health measure are still common. this is discussed in chapter . equally important is the public health policy issue of resource allocation and taxation for health purposes. taxation is an unpopular measure that governments must employ and enforce in order to do the public's business. the debate over the patient protection and affordable care act (ppaca or "obamacare"), discussed elsewhere in this and other chapters, shows how bitter the arguments can become, yet the goal of equality of access to health care cannot be denied as a public good, demonstrably contributing to the health of the nation. primary prevention refers to those activities that are undertaken to prevent disease or injury from occurring at all. primary prevention works with both the individual and the community. it may be directed at the host to increase resistance to the agent (such as in immunization or cessation of smoking), or at environmental activities to reduce conditions favorable to the vector for a biological agent, such as mosquito vectors of malaria or dengue fever. landmark examples include the treatment and prevention of scurvy among sailors based on james lind's findings in a classic clinical epidemiological study in , and john snow's removal of the handle from the broad street pump to stop a cholera epidemic in london in (see chapter ). primary prevention includes elements of health protection such as ensuring water, food and drug, and workplace safety; chlorination of drinking water to prevent transmission of waterborne enteric diseases; pasteurization of milk to prevent gastrointestinal diseases; mandating wearing seat belts in motor vehicles to prevent serious injury and death in road crashes; and reducing the availability of firearms to reduce injury and death from intentional, accidental, or random violence. it also includes direct measures to prevent diseases, such as immunization to prevent polio, tetanus, pertussis, and diphtheria. health promotion and health protection blend together as a group of activities that reduce risk factors and diseases through many forms of intervention such as changing smoking legislation or preventing birth defects by fortification of flour with folic acid. prevention of hiv transmission by needle exchange for intravenous drug users, promoting condom usage, and promoting male circumcision in africa, and the distribution of condoms and clean needles for hivpositive drug users are recent examples of primary prevention associated with health promotion programs. primary prevention also includes activities within the health system that can lead to better health. this may mean, for example, setting standards and to reduce hospital infections, and ensuring that doctors not only are informed of appropriate immunization practices and modern prenatal care or screening programs for cancer of the cervix, colon, and breast, but also are aware of their vital role in preventing cardiovascular and other non-communicable diseases. in this role, the health care provider serves as a teacher and guide, as well as a diagnostician and therapist. like health promotion, primary prevention does not depend on health care providers alone; health promotion works to increase individual and community consciousness of self-care, mainly by raising awareness and information levels and empowering the individual and the community to improve self-care, to reduce risk factors, and to live healthier lifestyles. secondary prevention is early diagnosis and management to prevent complications from a disease. public health interventions to prevent the spread of disease include the identification of sources of the disease and the implementation of steps to stop it, as shown in snow's closure of the broad street pump. secondary prevention includes steps to isolate cases and treat or immunize contacts so as to prevent further cases of meningitis or measles, for example, in outbreaks. for current epidemics such as hiv/aids, primary prevention is largely based on education, abstinence from any and certainly risky sexual behavior, circumcision, and treatment of patients in order to improve their health and to reduce the risk of spread of hiv. for high-risk groups such as intravenous drug users, needleexchange programs reduce the risk of spread of hiv, and hepatitis b and c. distribution of condoms to teenagers, military personnel, truck drivers, and commercial sex workers helps to prevent the spread of stis and aids in schools and colleges, as well as among the military. the promotion of circumcision is shown to be effective in reducing the transmission of hiv and of hpv (the causative organism for cancer of the cervix). all health care providers have a role in secondary prevention; for example, in preventing strokes by early identification and adequate care of hypertension. the child who has an untreated streptococcal infection of the throat may develop complications which are serious and potentially life-threatening, including rheumatic fever, rheumatic valvular heart disease, and glomerulonephritis. a patient found to have elevated blood pressure should be advised about continuing management by appropriate diet and weight loss if obese, regular physical exercise, and long-term medication with regular follow-up by a health provider in order to reduce the risk of stroke and other complications. in the case of injury, competent emergency care, safe transportation, and good trauma care may reduce the chance of death and/or permanent handicap. screening and high-quality care in the community prevent complications of diabetes, including heart, kidney, eye, and peripheral vascular disease. they can also prevent hospitalizations, amputations, and strokes, thus lengthening and improving the quality of life. health care systems need to be actively engaged in secondary prevention, not only as individual doctors' services, but also as organized systems of care. public health also has a strong interest in promoting highquality care in secondary and tertiary care hospital centers in such areas of treatment as acute myocardial infarction, stroke, and injury in order to prevent irreversible damage. measures include quality of care reviews to promote adequate longterm postmyocardial infarction care with aspirin and betablockers or other medication to prevent or delay recurrence and second or third myocardial infarctions. the role of highquality transportation and care in emergency facilities of hospitals in public health is vital to prevent long-term damage and disability; thus, cardiac care systems including publicly available defibrillators, catheterization, the use of stents, and bypass procedures are important elements of health care policy and resource allocation, which should be accessible not only in capital cities but also to regional populations. tertiary prevention involves activities directed at the host or patient, but also at the social and physical environment in order to promote rehabilitation, restoration, and maintenance of maximum function after the disease and its complications have stabilized. the person who has undergone a cerebrovascular accident or trauma will reach a stage where active rehabilitation can help to restore lost functions and prevent recurrence or further complications. the public health system has a direct role in the promotion of disability-friendly legislation and standards of building, housing, and support services for chronically ill, handicapped, and elderly people. this role also involves working with many governmental social and educational departments, but also with advocacy groups, ngos, and families. it may also include the promotion of disability-friendly workplaces and social service centers. treatment for conditions such as myocardial infarction or a fractured hip now includes early rehabilitation in order to promote early and maximum recovery with restoration to optimal function. the provision of a wheelchair, walkers, modifications to the home such as special toilet facilities, doors, and ramps, along with transportation services for paraplegics are often the most vital factors in rehabilitation. public health agencies work with groups in the community concerned with promoting help for specific categories of risk group, disease, or disability to reduce discrimination. community action is often needed to eliminate financial, physical, or social barriers, promote community awareness, and finance special equipment or other needs of these groups. close follow-up and management of chronic disease, physical and mental, require home care and ensuring an appropriate medical regimen including drugs, diet, exercise, and support services. the follow-up of chronically ill people to supervise the taking of medications, monitor changes, and support them in maximizing their independent capacity in activities of daily living is an essential element of the new public health. public health uses a population approach to achieve many of its objectives. this requires defining the population, including trends of change in the age and gender distribution of the population, fertility and birth rates, spread of disease and disability, mortality, marriage and migration, and socioeconomic factors. the reduction of infectious disease as the major cause of mortality, increased longevity coupled with declining fertility rates, resulted in changes in the age composition, or a demographic transition. demographic changes, such as fertility and mortality patterns, are important factors in changing the age distribution of the population, resulting in a greater proportion of people surviving to older ages. declining infant mortality, increasing educational levels of women, the availability of birth control, and other social and economic factors lead to changes in fertility patterns and the demographic transition -an aging of the population -with important effects on health service needs. the age and gender distribution of a population affects and is affected by patterns of disease. change in epidemiological patterns, or an epidemiological shift, is a change in predominant patterns of morbidity and mortality. the transition of infectious diseases becoming less prominent as causes of morbidity and mortality and being replaced by chronic and non-infectious diseases has occurred in both developed and developing countries. the decline in mortality from chronic diseases, such as cardiovascular disease, represents a new stage of epidemiological transition, creating an aging population with higher standards of health but also long-term community support and care needs. monitoring and responding to these changes are fundamental responsibilities of public health, and a readiness to react to new, local, or generalized changes in epidemiological patterns is vital to the new public health. societies are not totally homogeneous in ethnic composition, levels of affluence, or other social markers. on one hand, a society classified as developing may have substantial numbers of people with incomes that promote overnutrition and obesity, so that disease patterns may include increasing prevalence of diseases of excesses, such as diabetes. on the other hand, affluent societies include population groups with disease patterns of poverty, including poor nutrition and low birth-weight babies. a further stage of epidemiological transition has been occurring in the industrialized countries since the s, with dramatic reductions in mortality from chd, stroke and, to a lesser extent, trauma. the interpretation of this epidemiological transition is still not perfectly clear. how it occurred in the industrialized western countries but not in those of the former soviet union is a question whose answer is vital to the future of health in russia and some countries of eastern europe. developing countries must also prepare to cope with increasing epidemics of non-infectious diseases, and all countries face renewed challenges from infectious diseases with antibiotic resistance or newly appearing infectious agents posing major public health threats. demographic change in a country may reflect social and political decisions and health system priorities from decades before. russia's rapid population decline since the s, china's gender imbalance with a shortage of millions of young women, egypt's rapid population growth outstripping economic capacity, and many other examples indicate the severity and societal importance of capacity to analyze and formulate public health and social policies to address such fundamental sociopolitical issues. aging of the population is now the norm in most developed countries as a result of low birth and declining mortality rates. this change in the age distribution of a population has many associated social and economic issues as to the future of social welfare with a declining age cohort to provide the workforce. the aging population requires pension and health care support which make demands of social security systems that will depend on economic growth with a declining workforce. in times of economic stress, as in europe, this situation is made more difficult by longstanding short working weeks, early pension ages, and high social benefits. however, this results in unemployment among young people in particular and social conflict. the interaction of increasing life expectancy and a declining workforce is a fundamental problem in the high-income countries. this imbalance may be resolved in part through productivity gains and switching of primary production to countries with large still underutilized workforces, while employment in the developed countries will depend on service industries including health and the economic growth generated by higher technology and intellectual property and service industries. the challenge of keeping populations and individuals healthy is reflected in modern health services. each component of a health service may have developed with different historical emphases, operating independently as a separate service under different administrative auspices and funding systems, competing for limited health care resources. in this situation, preventive community care receives less attention and resources than more costly treatment services. figure . suggests a set of health services in an interactive relationship to serve a community or defined population, but the emphasis should be on the interdependence of these services with one other and with the comprehensive network in order to achieve effective use of resources and a balanced set of services for the patient, the client or patient population, and the community. clinical medicine and public health each play major roles in primary, secondary, and tertiary prevention. each may function separately in their roles in the community, but optimal success lies in their integrated efforts. allocation of resources should promote management and planning practices to assist this integration. there is a functional interdependence of all elements of health care serving a definable population. the patient should be the central figure in the continuum or complex of services available. effectiveness in use of resources means that providing the service most appropriate for meeting the individual's or group's needs at a point in time are those that should be applied. this is the central concept in currently developing innovations in health care delivery in the usa with organizations using terms such as patient centered medical home, accountable care organizations (acos), and population health management systems, which are being promoted in the obamacare health reforms now in process (see chapter ) (shortell et al., ) . separate organization and financing of services place barriers to appropriate provision of services for both the community and the individual patient. the interdependence of services is a challenge in health care organizations for the future. where there is competition for limited resources, pressures for tertiary services often receive priority over programs to prevent children from dying of preventable diseases. public health must be seen in the context of all health care and must play an influential role in promoting prevention at all levels. clinical services need public health in order to provide prevention and community health services that reduce the burden of disease, disability, and dependence on the institutional setting. health was traditionally thought of as a state of absence of disease, pain, or disability, but has gradually been expanded to include physical, mental, and societal well-being. in , c. e. a. winslow, professor of public health at yale university, defined public health as follows: "public health is the science and art of ( ) preventing disease, ( ) prolonging life, and ( ) winslow's far-reaching definition remains a valid framework but is unfulfilled when clinical medicine and public health have financing and management barriers between them. in many countries, isolation from the financing and provision of medical and nursing care services left public health with the task of meeting the health needs of the indigent and underserved population groups with inadequate resources and recognition. health insurance organizations for medical and hospital care have in recent years been more open to incorporating evidence-based preventive care, but the organization of public health has lacked the same level of attention. in some countries, the limitations have been conceptual in that public health was defined primarily in terms of control of infectious, environmental, and occupational diseases. a more recent and widely used definition is: "public health is the science and art of preventing disease, prolonging life, and promoting health through the organized efforts of society." this definition, coined in in the public health in england report by sir donald acheson, reflects the broad focus of modern public health. terms such as social hygiene, preventive medicine, community medicine, and social medicine have been used to denote public health practice over the past century. preventive medicine is the application of preventive measures by clinical practitioners combining some elements of public health with clinical practice relating to individual patients. preventive medicine defines medical or clinical personal preventive care, with stress on risk groups in the community and national efforts for health promotion. the focus is on the health of defined populations to promote health and well-being using evidence-based guidelines for cost-effective preventive measures. measures emphasized include screening and follow-up of chronic illnesses, and immunization programs; for example, influenza and pneumococcal pneumonia vaccines are used by people who are vulnerable because of their age, chronic diseases, or risk of exposure, such as medical and nursing personnel and those providing other personal clinical services. clinical medicine also deals in the area of prevention in the management of patients with hypertension or diabetes, and in doing so prevents the serious complications of these diseases. social medicine is also primarily a medical specialty which looks at illness in an individual in the family and social context, but lacks the environmental and regulatory and organized health promotion functions of public health. community health implies a local form of health intervention, whereas public health more clearly implies a global approach, which includes action at the international, national, state, and local levels. some issues in health can be dealt with at the individual, family, or community level; others require global strategies and intervention programs with regional, national, or international collaboration and leadership. the social medicine movement originated to address the harsh conditions of the working population during the industrial revolution in mid-nineteenth-century europe. an eminent pioneer in cellular pathology, rudolph virchow provided leadership in social medicine powered by the revolutionary movements of , and subsequent social democrat political movements. their concern focused on harsh living and health conditions among the urban poor working class and neglectful political norms of the time. social medicine also developed as an academic discipline and advocacy orientation by providing statistical evidence showing, as in various governmental reports in the mid-nineteenth century, that poverty among the working class was associated with short life expectancy and that social conditions were key factors in the health of populations and individuals. this movement provided the basis for departments in medical faculties and public health education throughout the world stressing the close relationship between political priorities and health status. this continued in the twentieth century and in the usa found expression in pioneering work since the s at montefiore hospital in new york and with victor sidel, founding leader of the community health center movement the usa from the s. in the twenty-first century this movement continues to emphasize relationships between politics, society, disease, and medicine, and forms of medical practice derived from it, as enunciated by prominent advocates such as harvardbased paul farmer in haiti, russia and rwanda, and in the uk by martin mckee and others (nolte and mckee, ) . similar concepts are current in the usa under headings such as family medicine, preventive medicine, and social medicine. this movement has also influenced sir michael marmot and others in the world health commission of health inequalities of , with a strong influence on the un initiative to promote mdgs, whose first objective is poverty reduction (commission on inequalities report ). application of the idea of poverty reduction as a method of reducing health inequalities has been successful recently in a large field trial in brazil showing greater reduction in child mortality where cash bonuses were awarded by municipalities for the poor families than that observed in other similar communities (rasella, ). in the usa, this movement is supported by increased health insurance coverage for the working poor, with funding for preventive care and incentives for community health centers in the obamacare plan of for implementation in the coming years to provide care for uninsured and underserved populations, particularly in urban and rural poverty areas. the political aspect of social medicine is the formulation of and support for national initiatives to widen health care coverage to the percent of the us population who are still uninsured, and to protect those who are arbitrarily excluded owing to previous illnesses, caps on coverage allowed, and other exploitative measures taken by private insurance that frequently deny americans access to the high levels of health care available in the country. the ethical base of public health in europe evolved in the context of its successes in the nineteenth and early twentieth centuries along with ideas of social progress. but the twentieth century was also replete with extremism and wide-scale abuse of human rights, with mass executions, deportations, and starvation as official policy in fascist and stalinist regimes. eugenics, a pseudoscience popularized in the early decades of the twentieth century, promoted social policies meant to improve the hereditary qualities of a race by methods such as sterilization of mentally handicapped people. the "social and racial hygiene" of the eugenics movements led to the medicalization of sterilization in the usa and other countries. this was adopted and extended in nazi germany to a policy of murder, first of the mentally and physically handicapped and then of "racial inferiors". these eugenics theories were widely accepted in the medical community in germany, then used by the nazi regime to justify medically supervised killing of hundreds of thousands of helpless, incapacitated individuals. this practice was linked to wider genocide and the holocaust, with the brutalization and industrialized murder of over million jews and million other people, and corrupt medical experimentation on prisoners. following world war ii, the ethics of medical experimentation (and public health) were codified in the nuremberg code and universal declaration of human rights based on lessons learned from these and other atrocities inflicted on civilian populations (see chapter ). threats of genocide, ethnic cleansing, and terrorism are still present on the world stage, often justified by current warped versions of racial hygienic theories. genocidal incitement and actual genocide and terrorism have recurred in the last decades of the twentieth century and into the twenty-first century in the former yugoslav republics, africa (rwanda and darfur), south asia, and elsewhere. terrorism against civilians has become a worldwide phenomenon with threats of biological and chemical agents, and potentially with nuclear capacity. asymmetrical warfare of insurgencies which use innocent civilians for cover, as with other forms of warfare, carries with it grave dangers to public health, human rights, and international stability, as seen in the twenty-first century in south sudan, darfur, dr congo, chechnya, iraq, afghanistan, and pakistan. in , kerr white and colleagues defined medical ecology as population-based research providing the foundation for management of health care quality. this concept stresses a population approach, including those not attending and those using health services. this concept was based on previous work on quality of care, randomized clinical trials, medical audit, and structure-process-outcome research. it also addressed health care quality and management. these themes influenced medical research by stressing the population from which clinical cases emerge as well as public health research with clinical outcome measures, themes that recur in the development of health services research and, later, evidence-based medicine. this led to the development of the agency for health care policy and research and development in the us department of health and human services and evidence-based practice centers to synthesize fundamental knowledge for the development of information for decision-making tools such as clinical guidelines, algorithms, or pathways. clinical guidelines and recommended best practices have become part of the new public health to promote quality of patient care and public health programming. these can include recommended standards; for example, follow-up care of the postmyocardial infarction patient, an internationally recommended immunization schedule, recommended dietary intake or food fortification standards, and mandatory vitamin k and eye care for all newborns and many others (see chapter ). community-oriented primary care (copc) is an approach to primary health care that links community epidemiology and appropriate primary care, using proactive responses to the priority needs identified. copc, originally pioneered in south africa and israel by sidney and emily kark and colleagues in the s and s, stresses medical services in the community which need to be adapted to the needs of the population as defined by epidemiological analysis. copc involves community outreach and education, as well as clinical preventive and treatment services. copc focuses on community epidemiology and an active problem-solving approach. this differs from national or larger scale planning that sometimes loses sight of the local nature of health problems or risk factors. copc combines clinical and epidemiological skills, defines needed interventions, and promotes community involvement and access to health care. it is based on linkages between the different elements of a comprehensive basket of services along with attention to the social and physical environment. a multidisciplinary team and outreach services are important for the program, and community development is part of the process. in the usa, the copc concept has influenced health care planning for poor areas, especially provision of federally funded community health centers in attempts to provide health care for the underserved since the s. in more recent years, copc has gained wider acceptance in the usa, where it is associated with family physician training and community health planning based on the risk approach and "managed care" systems. indeed, the three approaches are mutually complementary (box . ). as the emphasis on health care reform in the late s moved towards managed care, the principles of copc were and will continue to be important in promoting health and primary prevention in all its modalities, as well as tertiary prevention with followup and maintenance of the health of the chronically ill. copc stresses that all aspects of health care have moved towards prevention based on measurable health issues in the community. through either formal or informal linkages between health services, the elements of copc are part of the daily work of health care providers and community services systems. the us institute of medicine issued the report on primary care in , defining primary care as "the provision of integrated, accessible health care services by clinicians who are accountable for addressing the majority of personal health care needs, developing a sustained partnership with patients and practicing in the context of the family and the community". this formulation was criticized by the american public health association (apha) as lacking a public health perspective and failing to take into account both the individual and the community health approaches. copc tries to bridge this gap between the perspectives of primary care and public health. the community, whether local, regional, or national, is the site of action for many public health interventions. moreover, understanding the characteristics of the community is vital to a successful community-oriented approach. by the s, new patterns of public health began to emerge, including all measures used to improve the health of the community, and at the same time working to protect and promote the health of the individual. the range of activities to achieve these general goals is very wide, including individual patient care systems and the community-wide activities that affect the health and well-being of the individual. these include the financing and management of health systems, evaluation of the health status of the population, and measures to improve the quality of health care. they place reliance on health promotion activities to change environmental risk factors for disease and death. they promote integrative and multisectoral approaches and the international health teamwork required for global progress in health. the definition of health in the charter of the who as a complete state of physical, mental, and social well-being had a ring of utopianism and irrelevance to states struggling to provide even minimal care in severely adverse political, economic, social, and environmental conditions (box . ). in , a more modest goal was set for attainment of a level of health compatible with maximum feasible social and economic productivity. one needs to recognize that health and disease are on a dynamic continuum that affects everyone. the mission for public health is to use a wide range of methods to prevent disease and premature death, and improve quality of life for the benefit of individuals and the community. the world health organization defines health as "a state of complete physical, mental and social well-being, not merely the absence of disease or infirmity" (who constitution, ) . in at the alma-ata conference on primary health care, the who related health to "social and economic productivity in setting as a target the attainment by all the people of the world of a level of health that will permit them to lead a socially and economically productive life". three general programs of work for the periods - , - , and - were formulated as the basis of national and international activity to promote health. in , the who, recognizing changing world conditions of demography, epidemiology, environment, and political and economic status, addressed the unmet needs of developing countries and health management needs in the industrialized countries, calling for international commitment to "attain targets that will make significant progress towards improving equity and ensuring sustainable health development". the object of the who is restated as "the attainment by all peoples of the highest possible level of health" as defined in the who constitution, by a wide range of functions in promoting technical cooperation, assisting governments, and providing technical assistance, international cooperation, and standards. in the s, most industrialized countries were concentrating energies and financing in health care on providing access to medical and hospital services through national insurance schemes. developing countries were often spending scarce resources trying to emulate this trend. the who was concentrating on categorical programs, such as eradication of smallpox and malaria, as well as the expanded program of immunization and similar specific efforts. at the same time, there was a growing concern that developing countries were placing too much emphasis and expenditure on curative services and not enough on prevention and primary care. the world health assembly (wha) in endorsed the primary care approach under the banner of "health for all by the year " (hfa ) . this was a landmark decision and has had important practical results. the who and the united nations children's fund (unicef) sponsored a seminal conference held in alma-ata, in the ussr ( kazakhstan), in , which was convened to refocus health policy on primary care. the alma-ata declaration stated that health is a basic human right, and that governments are responsible to assure that right for their citizens and to develop appropriate strategies to fulfill this promise. this proposition has come to be increasingly accepted in the international community. the conference stressed the right and duty of people to participate in the planning and implementation of their health care. it advocated the use of scientifically, socially, and economically sound technology. joint action through intersectoral cooperation was also emphasized. the alma-ata declaration focused on primary health care as the appropriate method of assuming adequate access to health care for all (box . ). many countries have gradually come to accept the notion of placing priority on primary care, resisting the temptation to spend high percentages of health care resources on high-tech and costly medicine. spreading these same resources into highly costeffective primary care, such as immunization and nutrition programs, provides greater benefit to individuals and to society as a whole. alma-ata provided a new sense of direction for health policy, applicable to developing countries and in a different way than the approaches of the developed countries. during the s, the health for all concept influenced national health policies in the developing countries with signs of progress in immunization coverage, for example, but the initiative was diluted as an unintended consequence by more categorical programs such as eradication of poliomyelitis. for example, developing countries have accepted immunization and diarrheal disease control as high-priority issues and achieved remarkable success in raising immunization coverage from some percent to over percent in just a decade. developed countries addressed these principles in different ways. in these countries, the concept of primary health care led directly to important conceptual developments in health. national health targets and guidelines are now common in many countries and are integral parts of box . declaration of alma-ata, : a summary of primary health care (phc) . reaffirms that health is a state of complete physical, mental, and social well-being, and not merely the absence of disease or infirmity, and is a fundamental human right. existing gross inequalities in the health status of the people, particularly between developed and developing countries as well as within countries, are of common concern to all countries. . governments have a responsibility for the health of their people. the people have the right and duty to participate in planning and implementation of their health care. . a main social target is the attainment, by all peoples of the world by the year , of a level of health that will permit them to lead a socially and economically productive life. . phc is essential health care based on practical, scientifically sound, and socially acceptable methods and technology. . it is the first level of contact of individuals, the family, and the national health system bringing health care as close as possible to where people live and work, as the first element of a continuing health care process. . phc evolves from the conditions and characteristics of the country and its communities, based on the application of social, biomedical, and health services research and public health experience. . phc addresses the main health problems in the community, providing promotive, preventive, curative, and rehabilitative services accordingly. . phc includes the following: (a) education concerning prevailing health problems and methods of preventing and controlling them (b) promotion of food supply and proper nutrition (c) adequate supply of safe water and basic sanitation (d) maternal and child health care, including family planning (e) immunization against the major infectious diseases (f) prevention of locally endemic diseases (g) appropriate treatment of common diseases and injuries (h) the provision of essential drugs (i) relies on all health workers … to work as a health team. . all governments should formulate national health policies, strategies and plans, mobilize political will and resources, used rationally, to ensure phc for all people. national health planning. reforms of the nhs -for example, as discussed in chapter , remuneration increases for family physicians and encouraging group practice with public health nursing support -have become widespread in the uk. leading health maintenance organizations, such as kaiser permanente in the usa and district health systems in canada, have emphasized integrated approaches to health care for registered or geographically defined populations (see chapters - ). this approach is becoming common in the usa in acos, which will be fostered by the obamacare legislation (ppaca). this systematic approach to individual and community health is an integral part of the new public health. the interactions among community public health, personal health services, and health-related behavior, including their management, are the essence of the new public health. how the health system is organized and managed affects the health of the individual and the population, as does the quality of providers. health information systems with epidemiological, economic, and sociodemographic analysis are vital to monitor health status and allow for changing priorities and management. well-qualified personnel are essential to provide services, manage the system, and carry out relevant research and health policy analysis. diffusion of data, health information, and responsibility helps to provide a responsive and comprehensive approach to meet the health needs of the individual and community. the physical, social, economic, and political environments are all important determinants of the health status of the population and the individual. joint action (intersectoral cooperation) between public and non-governmental or community-based organizations is needed to achieve the well-being of the individual in a healthy society. in the s and s, these ideas contributed to an evolving new public health, spurred on by epidemiological changes, health economics, the development of managed care linking health systems, and prepayment. knowledge and self-care skills, as well as community action to reduce health risks, are no less important in this than the roles of medical practitioners and institutional care. all are parts of a coherent holistic approach to health. the concept of selective primary care, articulated in by walsh and warren, addresses the needs of developing countries to select those interventions on a broad scale that would have the greatest positive impact on health, taking into account limited resources such as money, facilities, and human resources. the term selective primary care is meant to define national priorities that are based not on the greatest causes of morbidity or mortality, but on common conditions of epidemiological importance for which there are effective and simple preventive measures. throughout health planning, there is an implicit or explicit selection of priorities for allocation of resources. even in primary care, selection of targets is a part of the process of resource allocation. in modern public health, this process is more explicit. a country with limited resources and a high birth rate will emphasize maternal and child health before investing in geriatric care. this concept has become part of the microeconomics of health care and technology assessment, discussed in chapters and , respectively, and is used widely in setting priorities and resource allocation. in developing countries, cost-effective primary care interventions have been articulated by many international organizations, including iodization of salt, use of oral rehydration therapy (ort) for diarrheal diseases, vitamin a supplementation for all children, expanded programs of immunization, and others that have the potential for saving hundreds of thousands of lives yearly at low cost. in developed countries, health promotions targeted to reduce accidents and risk factors such as smoking, high-fat diets, and lack of exercise for cardiovascular diseases are low-cost public health interventions that save lives and reduce the use of hospital care. targeting specific diseases is essential for efforts to control tb or eradicate polio, but at the same time, development of a comprehensive primary care infrastructure is equally or even more important than the single-disease approach. some disease entities such as hiv/aids attract donor funding more readily than basic infrastructure services such as immunization, and this can sometimes be detrimental to addressing the overall health needs of the population and other neglected but also important diseases. the risk approach selects population groups on the basis of risk and helps to determine interventional priorities to reduce morbidity and mortality. the measure of health risk is taken as a proxy for need, so that the risk approach provides something for all, but more for those in need, in proportion to that need. in epidemiological terms, these are people with higher relative risk or attributed risk. some groups in the general population are at higher risk than others for specific conditions. the expanded programme on immunization (epi), control of diarrhoeal diseases (cdd), and acute respiratory disease (ard) programs of the who are risk approaches to tackling fundamental public health problems of children in developing countries. public health places considerable emphasis on maternal and child health because these are vulnerable periods in life for specific health problems. pregnancy care is based on a basic level of care for all, with continuous assessment of risk factors that require a higher intensity of follow-up. prenatal care helps to identify factors that increase the risk for the pregnant woman or her fetus/newborn. efforts directed towards these special risk groups have the potential to reduce morbidity and mortality. high-risk case identification, assessment, and management are vital to a successful maternal care program. similarly, routine infant care is designed not only to promote the health of infants, but also to find the earliest possible indications of deviation and the need for further assessment and intervention to prevent a worsening of the condition. low birth-weight babies are at greater risk for many short-and long-term hazards and should be given special treatment. all babies are routinely screened for birth defects or congenital conditions such as hypothyroidism, phenylketonuria, and other metabolic and hematological diseases. screening must be followed by investigating and treating those found to have a clinical deficiency. this is an important element of infant care because infancy itself is a risk factor. as will be discussed in chapters and and others, epidemiology has come to focus on the risk approach with screening based on known genetic, social, nutritional, environmental, occupational, behavioral, or other factors contributing to the risk for disease. the risk approach has the advantage of specificity and is often used to initiate new programs directed at special categories of need. this approach can lead to narrow and somewhat rigid programs that may be difficult to integrate into a more general or comprehensive approach, but until universal programs can be achieved, selective targeted approaches are justifiable. indeed, even with universal health coverage, it is still important to address the health needs or issues of groups at special risk. working to achieve defined targets means making difficult choices. the supply and utilization of some services will limit availability for other services. there is an interaction, sometimes positive, sometimes negative, between competing needs and the health status of a population. public health identifies needs by measuring and comparing the incidence or prevalence of the condition in a defined population with that in other comparable population groups and defines targets to reduce or eliminate the risk of disease. it determines ways of intervening in the natural epidemiology of the disease, and develops a program to reduce or even eliminate the disease. it also assesses the outcomes in terms of reduced morbidity and mortality, as well as the economic justification in cost-effectiveness analysis to establish its value in health priorities. because of the interdependence of health services, as well as the total financial burden of health care, it is essential to look at the costs of providing health care, and how resources should be allocated to achieve the best results possible. health economics has become a fundamental methodology in policy determination. the costs of health care, the supply of services, the needs for health care or other health-promoting interventions, and effective means of using resources to meet goals are fundamental in the new public health. it is possible to err widely in health planning if one set of factors is overemphasized or underemphasized. excessive supply of one service diminishes the availability of resources for other needed investments in health. if diseases are not prevented or their sequelae not well managed, patients must use costly health care services and are unable to perform their normal social functions such as learning at school or performing at work. lack of investment in health promotion and primary prevention creates a larger reliance on institutional care, driving health costs upwards, and restricting flexibility in meeting patients' needs. the interaction of supply and demand for health services is an important determinant of the political economy of health care. health and its place in national priorities are determined by the social-political philosophy and resource allocation of a government. the case for action, or the justification for a public health intervention, is a complex of epidemiological, economic, and public policy factors (table . ). each disease or group of diseases requires its own case for action. the justification for public health intervention requires sufficient evidence of the incidence and prevalence of the disease (see chapter ). evidence-based public health takes into account the effectiveness and safety of an intervention; risk factors; safe means at hand to intervene; the human, social, and economic cost of the disease; political factors; and a policy decision as to the priority of the problem. this often depends on subjective factors, such as the guiding philosophy of the health system and the way it allocates resources. some interventions are so well established that no new justification is required to make the case, and the only question is how to do it most effectively. for example, infant vaccination is a cost-effective and cost-beneficial program for the protection of the individual child and the population as a whole. whether provided as a public service or as a clinical preventive measure by a private medical practitioner, it is in the interest of public health that all children be immunized. an outbreak of diarrheal disease in a kindergarten presents an obvious case for action, and a public health system must respond on an emergency basis, with selection of the most suitable mode of intervention. the considerations in developing a case for action are outlined above. need is based on clinical and epidemiological evidence, but also on the importance of an intervention in the eyes of the public. the technology available, its effectiveness and safety, and accumulated experience are important in the equation, as are the acceptability and affordability of appropriate interventions. the precedents for use of an intervention are also important. on epidemiological evidence, if the preventive practice has been seen to provide reduction in risk for the individual and for the population, then there is good reason to implement it. the costs, risks and benefits must be examined as part of the justification to help in the selection of health priorities. health systems research examines the efficiency of health care and promotes improved efficiency and effective use of resources. this is a vital function in determining how best to use resources and meet current health needs. past emphasis on hospital care at the expense of less development of primary care and prevention is still a common issue, particularly in former soviet and developing countries, where a high percentage of total health expenditure goes to acute hospital care with long length of stay, with smaller allocation to preventive and community health care. the result of this imbalance is high mortality from preventable diseases. new drugs, vaccines, and medical equipment are continually becoming available, and each new addition needs to be examined among the national health priorities. sometimes, owing to cost, a country cannot afford to add a new vaccine to the routine. however, when there is good evidence for efficacy and safety of new vaccines, drugs, diagnostic methods or other innovations, it could be applied for those at greatest risk. although there are ethical issues involved, it may be necessary to advise parents or family members to purchase the vaccine independently. clearly, recommending individual purchase of a vaccine is counter to the principle of equity and solidarity, benefiting middleclass families, and providing a poor basis of data for evaluation of the vaccine and its target disease. on the other hand, failure to advise parents of potential benefits to their children creates other ethical problems, but may increase public pressure and insurance system acceptance of new methods, e.g., varicella and hpv vaccines. mass screening programs involving complete physical examinations have not been found to be cost-effective or to significantly reduce disease. in the s and s, routine general health examinations were promoted as an effective method of finding disease early. since the late s, a selective and specific approach to screening has become widely accepted. this involves defining risk categories for specific diseases and bearing in mind the potential for remedial action. early case finding of colon cancer by routine fecal blood testing and colonoscopy has been found to be effective, and pap smear testing to discover cancer of the cervix is timed according to risk category. screening for colorectal cancer is essential for modern health programs and has been adopted by most industrialized countries. outreach programs by visits, telephones, emails or other modern methods of communication are important to contact non-attenders to promote utilization, and have been shown to increase compliance with proven effective measures. these programs are important for screening, follow-up, and maintenance of treatment for hypertension, diabetes, and other conditions requiring long-term management. screening technology is changing and often the subject of intense debate as such programs are costly and their cost-effectiveness is an important matter for policy making: screening for lung cancer is becoming a feasible and effective matter for high-risk groups, whereas breast cancer screening frequency is now in dispute; while nanotechnology and bioengineering promises new methods for cancer screening. the factor of contribution to quality of life should be considered. a vaccine for varicella is justified partly for the prevention of deaths or illness from chickenpox. a stronger the right to health public expectation and social norms argument is often based on the fact that this is a disease that causes moderate illness in children for up to weeks and may require parents to stay home with the child, resulting in economic loss to the parent and society. the fact that this vaccination prevents the occurrence of herpes zoster or shingles later in life may also be a justification. widespread adoption of hepatitis b vaccine is justified on the grounds that it prevents cancer of the liver, liver cirrhosis, and hepatic failure in a high percentage of the population affected. how many cases of a disease are enough to justify an intervention? one or several cases of some diseases, such as poliomyelitis, may be considered an epidemic in that each case constitutes or is an indicator of a wider threat. a single case of polio suggests that another persons are infected but have not developed a recognized clinical condition. such a case constitutes a public health emergency, and forceful organization to meet a crisis is needed. current standards are such that even one case of measles imported into a population free of the disease may cause a large outbreak, as occurred in the uk, france, and israel during through , by contacts on an aircraft, at family gatherings, or even in medical settings. a measles epidemic indicates a failure of public health policy and practice. screening for some cancers, such as cervix and colon, is cost effective. screening of all newborns for congenital disorders is important because each case discovered early and treated effectively saves a lifetime of care for serious disability. assessing a public health intervention to prevent the disease or reduce its impact requires measurement of the disease in the population and its economic impact. there is no simple formula to justify a particular intervention, but the cost-benefit approach is now commonly required to make such a case for action. sometimes public opinion and political leadership may oppose the views of the professional community, or may impose limitations of policy or funds that prevent its implementation. conversely, professional groups may press for additional resources that compete for limited resources available to provide other needed health activities. both the professionals of the health system and the general public need full access to health-related information to take part in such debates in a constructive way. to maintain progress, a system must examine new technologies and justify their adoption or rejection (see chapter ). the association between health and political issues was emphasized by european innovators such as rudolf virchow (and in great britain by edwin chadwick; see chapter ) in the mid-nineteenth century, when the conditions of the working population were such that epidemic diseases were rife and mortality was high, especially in the crowded slums of the industrial revolution. the same observations led bismarck in germany to introduce early forms of social insurance for the health of workers and their families in the s, and to britain's national health insurance, also for workers and families. the role of government in providing universal access to health care was a struggle in individual countries during the twentieth century and lasting into the second decade of the twenty-first century (e.g. president obama's affordable health care act of ). as the concept of public health has evolved, and the cost effectiveness of medical care has improved through scientific and technological advances, societies have identified health as a legitimate area of activity for collective bargaining and government. with this process, the need to manage health care resources has become more clearly defined as a public responsibility. in industrialized countries, each with very different political make-up, national responsibility for universal access to health has become part of the social ethos. with that, the financing and managing of health services have developed into part of a broad concept of public health, and economics, planning, and management have come to be part of the new public health (discussed in chapters - ). social, ethical, and political philosophies have profound effects on policy decisions including allocation of public monies and resources. investment in public health is now recognized as an integral part of socioeconomic development. governments are major suppliers of funds and leadership in health infrastructure development, provision of health services, and health payment systems. they also play a central role in the development of health promotion and regulation of the environment, food, and drugs essential for community health. in liberal social democracies, the individual is deemed to have a right to health care. the state accepts responsibility to ensure availability, accessibility, and quality of care. in many developed countries, government has also taken responsibility to arrange funding and services that are equitably accessible and of high quality. health care financing may involve taxation, allocation, or special mandatory requirements on employers to pay for health insurance. services may be provided by a state-financed and -regulated service or through ngos and/or private service mechanisms. these systems allocate between percent and percent of gross national product (gnp) to health services, with some governments funding over percent of health expenditure; for example, canada and the uk. in communist states, the state organizes all aspects of health care with the philosophy that every citizen is entitled to equity in access to health services. the state health system manages research, staff training, and service delivery, even if operational aspects are decentralized to local health authorities. this model applied primarily to the soviet model of health services. these systems, except for cuba, placed financing of health low on the national priority, with funding less than percent of gnp. in the shift to market economies in the s, some former socialist countries, such as russia, are struggling with poor health status and a difficult shift from a strongly centralized health system to a decentralized system with diffusion of powers and responsibilities. promotion of market concepts in former soviet countries has reduced access to care and created a serious dilemma for their governments. former colonial countries, independent since the s and s, largely carried on the governmental health structures established in the colonial times. most developing countries have given health a relatively low place in budgetary allotment, with expenditures under percent of gnp. since the s, there has been a trend in developing countries towards decentralization of health services and greater roles for ngos, and the development of health insurance. some countries, influenced by medical concepts of their former colonial master countries, fostered the development of specialty medicine in the major centers with little emphasis on the rural majority population. soviet influence in many ex-colonial countries promoted state-operated systems. the who promoted primary care, but the allocations favored city-based specialty care. israel, as an ex-colony, adapted british ideas of public health together with central european sick funds and maternal and child health as major streams of development until the mid- s. a growing new conservatism in the s and s in the industrialized countries is a restatement of old values in which market economics and individualistic social values are placed above concepts of the "common good" of liberalism and socialism in its various forms. in the more extreme forms of this concept, the individual is responsible for his or her own health, including payment, and has a choice of health care providers that will respond with high-quality personalized care. market forces, meaning competition in financing and provision of health services with rationing of services, based on fees or private insurance and willingness and ability to pay, have become part of the ideology of the new conservatism. it is assumed that the patient (i.e., the consumer) will select the best service for his or her need, while the provider best able to meet consumer expectations will thrive. in its purest form, the state has no role in providing or financing of health services except those directly related to community protection and promotion of a healthful environment without interfering with individual choices. the state ensures that there are sufficient health care providers and allows market forces to determine the prices and distribution of services with minimal regulation. the usa retains this orientation in a highly modified form, with percent of the population covered by some form of private or public insurance systems (see chapters and ). modified market forces in health care are part of health reforms in many countries as they seek not only to ensure quality health care for all but also to constrain costs. a free market in health care is costly and ultimately inefficient because it encourages inflation of provider incomes or budgets and increasing utilization of highly technical services. further, even in the most free market societies, the economy of health care is highly influenced by many factors outside the control of the consumer and provider. the total national health expenditure in the usa rose rapidly until reaching over . percent of gross domestic product (gdp) in , the highest of any country, despite serious deficiencies for those without any or with very inadequate health insurance (in total more than percent of the population). this figure compares to some . percent of gdp in canada, which has universal health insurance under public administration. following the defeat of president clinton's national health program, the conservative congress and the business community took steps to expand managed care in order to control costs, resulting in a revolution in health care in the usa (see chapters and ). in the - decade health expenditure in the usa is expected to rise to . percent of gdp, partly owing to increased population coverage with implementation of the ppaca (obamacare). reforms are being implemented in many "socialized" health systems. these may be through incentives to promote achievement of performance indicators, such as full immunization coverage. others are using control of supply, such as hospital beds or licensed physicians, as methods of reducing overutilization of services that generates increasing costs. market mechanisms in health are aimed not only at the individual but also at the provider. incentive payment systems must work to protect the patient's legitimate needs, and conversely incentives that might reduce quality of care should be avoided. fee-for-service promotes high rates of services such as surgery. increasing private practice and user fees can adversely affect middle-and low-income groups, as well as employers, by raising the costs of health insurance. managed care systems, with restraints on fee-for-service medical practice, have emerged as a positive response to the market approach. incentive systems in payments for services may be altered by government or insurance agencies in order to promote rational use of services, such as reduction of hospital stays. the free market approach is affecting planning of health insurance systems in previously highly centralized health systems in developing countries as well as the redevelopment of health systems in former soviet countries. despite political differences, reform of health systems has become a common factor in virtually all health systems since the s, as each government searches for costeffectiveness, quality of care, and universality of coverage. the new paradigm of health care reform sees the convergence of different systems to common principles. national responsibility for health goals and health promotion leads to national financing of health care with regional and managed care systems. most developed countries have long since adopted national health insurance or service systems. some governments may, as in the usa, insure only the highest risk groups such as the elderly and the poor, leaving the working and middle classes to seek private insurers. the nature and direction of health care reform affecting coverage of the population are of central importance in the new public health because of its effects on allocation of resources and on the health of the population. the effects of the economic crisis in the usa are being felt worldwide. while the downturn has largely occurred in wealthier nations, the poor in low-income countries will be among those affected. past economic downturns have been followed by substantial drops in foreign aid to developing countries. as public health gained from sanitary and other control measures for infectious diseases, along with mother and child care, nutrition, and environmental and occupational health, it also gained strength and applicability from advances in the social and behavioral sciences. social darwinism, a political philosophy that assumed "survival of the fittest" and no intervention of the sate to alleviate this assumption, was popular in the early nineteenth century but became unacceptable in industrialized countries, which adopted social policies to alleviate the worst conditions of poverty, unemployment, poor education, and other societal ills. the political approach to focusing on health and poverty is associated with jeremy bentham in britain in the late eighteenth century, who promoted social and political reform and "the greatest good for the greatest number", or utilitarianism. rudolf virchow, an eminent pathologist and a leader in recognizing ill-health and poverty as cause and effect, called for political action to create better conditions for the poor and working-class population. the struggle for a social contract was promoted by pioneer reformists such as edwin chadwick (general report on the sanitary condition of the labouring population of great britain, ), who later became the first head of the board of health in britain, and lemuel shattuck (report of a general plan for the promotion of public and personal health, ) . shattuck was the organizer and first president of the american statistical association. the social sciences have become fundamental to public health, with a range of disciplines including vital statistics and demography (seventeenth century), economics and politics (nineteenth century), sociology (twentieth century), history, anthropology, and others, which provide collectively important elements of epidemiology of crucial significance for survey methods and qualitative research (see chapter ). these advances contributed greatly to the development of methods of studying diseases and risk factors in a population and are still highly relevant to addressing inequalities in health. individuals in good health are better able to study and learn, and be more productive in their work. improvements in the standard of living have long been known to contribute to improved public health; however, the converse has not always been recognized. investment in health care was not considered a high priority in many countries where economic considerations directed investment to the "productive" sectors such as manufacturing and large-scale infrastructure projects, such as hydroelectric dams. whether health is a contributor to economic development or a drain on societies' resources has been a fundamental debate between socially and market-oriented advocates. classic economic theory, both free enterprise and communist, has tended to regard health as a drain on economies, distracting investment needed for economic growth. as a result, in many countries health has been given low priority in budgetary allocation, even when the major source of financing is governmental. this belief among economists and banking institutions prevented loans for health development on the grounds that such funds should focus on creating jobs and better incomes, before investing in health infrastructure. consequently, the development of health care has been hampered. a socially oriented approach sees investment in health as necessary for the protection and development of "human capital", just as investment in education is needed for the long-term benefit of the economy of a country. in , the world bank's world development report: investing in health articulated a new approach to economics in which health, along with education and social development, is seen as an essential precondition for and contributor to economic development. while many in the health field have long recognized the importance of health for social and economic improvement, its adoption by leading international development banking may mark a turning point for investment in developing nations, so that health may be a contender for increased development loans. the concept of an essential package of services discussed in that report establishes priorities in low-and middle-income countries for efficient use of resources based on the burden of disease and cost-effectiveness analysis of services. it includes both preventive and curative services targeted to specific health problems. it also recommends support for comprehensive primary care, such as for children, and infrastructure development including maternity and hospital care, medical and nursing outreach services, and community action to improve sanitation and safe water supplies. reorientation of government spending on health is increasingly being adopted, as in the uk, to improve equity in access for the poor and other neglected sectors or regions of society with added funding for relatively deprived areas to improve primary care services. differential capitation funding as a form of affirmative action to provide for highneeds populations is a useful concept in public health terms to address the inequities still prevalent in many countries. as medical care has gradually become more involved in prevention, and as it has moved into the era of managed care, the gap between public health and clinical medicine has narrowed. as noted above, many countries are engaged in reforms in their health care systems. the motivation is largely derived from the need for cost containment, but also to extend health care coverage to underserved parts of the population. countries without universal health care still have serious inequities in distribution of or access to services, and may seek reform to reduce those inequities, perhaps under political pressures to improve the provision of services. incentives for reform are needed to address regional inequities, and preserving or developing universal access and quality of care, but also on inequities in health between the rich and the poor countries and within even the wealthy countries. in some settings, a health system may fail to keep pace with developments in prevention and in clinical medicine. some countries have overdeveloped medical and hospital care, neglecting important initiatives to reduce the risk of disease. the process of reform requires setting standards to measure health status and the balance of services to optimize health. a health service can set a target of immunizing percent of infants with a national immunization schedule, but requires a system to monitor performance and incentives for changes. a health system may also have failed to adapt to changing needs of the population through lack, or misuse, of health information and monitoring systems. as a result, the system may err seriously in its allocation of resources, with excessive emphasis on hospital care and insufficient attention to primary and preventive care. all health services should have mechanisms for correctly gathering and analyzing needed data for monitoring the incidence of disease and other health indicators, such as hospital utilization, ambulatory care, and preventive care patterns. for example, the uk's nhs periodically undertakes a restructuring process of parts of the system to improve the efficiency of service. this involves organizational changes and decentralization with regional allocation of resources (see chapter ). health systems are under pressures of changing demographic and epidemiological patterns as well as public expectations, rising costs of new technology, financing, and organizational change. new problems must be continually addressed with selection of priority issues and the most effective methods chosen. reforms may create unanticipated problems, such as professional or public dissatisfaction, which must be evaluated, monitored, and addressed as part of the evolution of public health. literacy, freedom of the press, and increasing public concern for social and health issues have contributed to the development of public health. the british medical community lobbied for restrictions on the sale of gin in the s in order to reduce the damage that it caused to the working class. in the late eighteenth and the nineteenth centuries, reforms in society and sanitation were largely the result of strongly organized advocacy groups influencing public opinion through the press. such pressure stimulated governments to act in regulating the working conditions of mines and factories. abolition of the slave trade and its suppression by the british navy in the early nineteenth century resulted from successful advocacy groups and their effects on public opinion through the press. vaccination against smallpox was promoted by privately organized citizen groups, until later taken up by local and national government authorities. advocacy consists of activities of individuals or groups publicly pleading for, supporting, espousing, or recommending a cause or course of action. the advocacy role of reform movements in the nineteenth century was the basis of the development of modern organized public health. campaigns ranged from the reform of mental hospitals, nutrition for sailors to prevent scurvy and beriberi, and labor laws to improve working conditions for women and children in particular, to the promotion of universal education and improved living conditions for the working population. reforms on these and other issues resulted from the stirring of the public consciousness by advocacy groups and the public media, all of which generated political decisions in parliaments (box . ). such reforms were in large part motivated by fear of revolution throughout europe in the mid-nineteenth century and the early part of the twentieth century. trade unions, and before them medieval guilds, fought to improve hours, safety, and conditions of work, as well as social and health benefits for their members. in the usa, collective bargaining through trade unions achieved wage increases and widespread coverage of the working population under voluntary health insurance. unions and some industries pioneered prepaid group practice, the predecessor of health maintenance organizations and managed care or the more recent acos (see chapters and ). through raising public consciousness on many issues, advocacy groups pressure governments to enact legislation to restrict smoking in public places, prohibit tobacco advertising, and mandate the use of bicycle helmets. advocacy groups play an important role in advancing health based on disease groups, such as cancer, multiple sclerosis, and thalassemia, or advancing health issues, such as the organizations promoting breastfeeding, environmental improvement, or smoking reduction. some organizations finance services or facilities not usually provided within insured health programs. such organizations, which can number in the hundreds in a country, advocate the importance of their special concern and play an important role in innovation and meeting community health needs. advocacy groups, including trade unions, professional groups, women's groups, self-help groups, and many others, focus on specific issues and have made major contributions to advancing the new public health. the history of public health is replete with pioneers whose discoveries led to strong opposition and sometimes violent rejection by conservative elements and vested interests in medical, public, or political circles. opposition to jennerian vaccination, the rejection of semmelweiss by colleagues in vienna, and the contemporary opposition to the work of great pioneers in public health such as pasteur, florence nightingale, and many others may deter or delay implementation of other innovators and new breakthroughs in preventing disease. although opposition to jenner's vaccination lasted well into the late nineteenth century in some areas, its supporters gradually gained ascendancy, ultimately leading to the global eradication of smallpox. these and other pioneers led the way to improved health, often after bitter controversy on topics later accepted and which, in retrospect, seem to be obvious. advocacy has sometimes had the support of the medical profession but elicited a slow response from public authorities. david marine of the cleveland clinic and david cowie, professor of pediatrics at the university of michigan, proposed the prevention of goiter by iodization of salt. marine carried out a series of studies in fish, and then in a controlled clinical trial among schoolgirls in - , with startlingly positive results in reducing the prevalence of goiter. cowie campaigned for the iodization of salt, with support from the medical profession. in , he convinced a private manufacturer to produce morton's iodized salt, which rapidly became popular throughout north america. similarly, iodized salt came to be used in many parts of europe, mostly without governmental support or legislation. iodine-deficiency disorders (idds) remain a widespread condition, estimated to have affected billion people worldwide in . the target of international eradication of idds by was set at the world summit for children in , and the who called for universal iodization of salt in . by , nearly percent of households in developing countries consumed adequately iodized salt. china and nigeria, have had great success in recent years with mandatory salt fortification in increasing iodization rates, in china from percent to percent in years. but the problem is not yet gone and even in europe there is inadequate standardization of iodine levels and population follow-up despite decades of work on the problem. professional organizations have contributed to promoting causes such as children's and women's health, and environmental and occupational health. the american academy of pediatrics has contributed to establishing and promoting high standards of care for infants and children in the usa, and to child health internationally. hospital accreditation has been used for decades in the usa, canada, and more recently in australia and the uk. it has helped to raise standards of health facilities and care by carrying out systematic peer review of hospitals, nursing homes, primary care facilities, and mental hospitals, as well as ambulatory care centers and public health agencies (see chapter ). public health needs to be aware of negative advocacy, sometimes based on professional conservatism or economic self-interest. professional organizations can also serve as advocates of the status quo in the face of change. opposition by the american medical association (ama) and the health insurance industry to national health insurance in the usa has been strong and successful for many decades. the passage of the ppaca has been achieved despite widespread political and public opposition, yet was sustained in the us supreme court and is gaining widening popular support as the added value to millions of formerly uninsured americans becomes clear. in some cases, the vested interest of one profession may block the legitimate development of others, such as when ophthalmologists lobbied successfully against the development of optometry, now widely accepted as a legitimate profession. political activism for reform in nineteenth-century britain led to banning and suppressing the slave trade, improvements in working conditions for miners and factory workers, and other major political reforms. in keeping with this tradition, samuel plimsoll ( - ), british member of parliament elected for derby in , conducted a solo campaign for the safety of seamen. his book, our seamen, described ships sent to sea so heavily laden with coal and iron that their decks were awash. seriously overloaded ships, deliberately sent to sea by unscrupulous owners, frequently capsized, drowning many crew members, with the owners collecting inflated insurance fees. overloading was the major cause of wrecks and thousands of deaths in the british shipping industry. plimsoll pleaded for mandatory load-line certificate markers to be issued to each ship to prevent any ships putting to sea when the marker was not clearly visible. powerful shipping interests fought him every inch of the way, but he succeeded in having a royal commission established, leading to an act of parliament mandating the "plimsoll line", the safe carrying capacity of cargo ships. this regulation was adopted by the us bureau of shipping as the load line act in and is now standard practice worldwide. jenner's discovery of vaccination with cowpox to prevent smallpox was adopted rapidly and widely. however, intense opposition by organized groups of antivaccinationists, often led by those opposed to government intervention in health issues and supported by doctors with lucrative variolation practices, delayed the implementation of smallpox vaccination for many decades. ultimately, smallpox was eradicated in , owing to a global campaign initiated by the who. opposition to legislated restrictions on private ownership of assault weapons and handguns is intense in the usa, led by well-organized, well-funded, and politically powerful lobby groups, despite the amount of morbidity and mortality due to gun-associated violent acts (see chapter ). fluoridation of drinking water is the most effective public health measure for preventing dental caries, but it is still widely opposed, and in some places the legislation has been rescinded even after implementation, by wellorganized antifluoridation campaigns. opposition to fluoridation of community water supplies is widespread, and effective lobbying internationally has slowed but has not stopped progress (see chapter ). despite the life-saving value of immunization, opposition still exists in and harms public health protection. opposition has slowed progress in poliomyelitis eradication; for example, radical islamists killed polio workers in northern nigeria in , one of the last three countries with endemic poliomyelitis. resistance to immunization in the s has resulted in the recurrence of pertussis and diphtheria and a very large epidemic of measles across western europe, including the uk, with further spread to the western hemisphere in - (see chapter ). progress may be blocked where all decisions are made in closed discussions, not subject to open scrutiny and debate. public health personnel working in the civil service of organized systems of government may not be at liberty to promote public health causes. however, professional organizations may then serve as forums for the essential professional and public debate needed for progress in the field. professional organizations such as the apha provide effective lobbying for the interests of public health programs and can have an important impact on public policy. in mid- , efforts by the secretary of health and human services in the usa brought together leaders of public health with representatives of the ama and academic medical centers to try to find areas of common interest and willingness to promote the health of the population. in europe too, increasing cooperation between public health organizations is stimulating debate on issues of transnational importance across the region, which, for example, has a wide diversity of standards on immunization practices and food policies. public advocacy has played an especially important role in focusing attention on ecological issues (box . ). in , greenpeace, an international environmental activist group, fought to prevent the dumping of an oil rig in the north sea and forced a major oil company to find another solution that would be less damaging to the environment. an explosion on an oil rig in the gulf of mexico in led to enormous ecological and economic damage as well as loss of life. damages levied on the responsible company (british petroleum) amount to some $ . billion dollars and several criminal negligence charges are pending. greenpeace also continued its efforts to stop the renewal of testing of atomic bombs by france in the south pacific. international protests led to the cessation of almost all testing of nuclear weapons. international concern over global warming has led to growing efforts to stem the tide of air pollution from fossil fuels, coal-burning electrical production, and other manifestations of carbon dioxide and toxic contamination of the environment. progress is far from certain as newly enriched countries such as china and india follow the rising consumption patterns of western countries. public advocacy and rejection of wanton destruction of the global ecology may be the only way to prod consumers, governments, and corporate entities such as the energy and transportation industries to change direction. the pace of change from fossil fuels is slow but has captured public attention, and private companies are seeking more fuel efficiency in vehicles and electrical power production, mainly though the use of natural gas instead of fuel oil and coal for electricity production or better still by wind and solar energy. the search for "green solutions" to the global warming crisis has become increasingly dynamic, with governments, the private sector, and the general public keenly aware of the importance of the effort and the dangers of failure. in the latter part of the twentieth century and the early twenty-first century, prominent international personalities and entertainers have taken up causes such as the removal of land mines in war-torn countries, illiteracy in disadvantaged advocacy is a function in public health that has been important in promoting advances in the field, and one that sometimes places the advocate in conflict with established patterns and organizations. one of the classic descriptions of this function is in henrik ibsen's play an enemy of the people, in which the hero, a young doctor, thomas stockmann, discovers that the water in his community is contaminated. this knowledge is suppressed by the town's leadership, led by his brother the mayor, because it would adversely affect plans to develop a tourist industry of baths in their small norwegian town in the late nineteenth century. the young doctor is taunted and abused by the townspeople and driven from the town, having been declared an "enemy of the people" and a potential risk. the allegory is a tribute to the man of principle who stands against the hysteria of the crowd. the term also took on a far more sinister and dangerous meaning in george orwell's novel and in totalitarian regimes of the s to the present time. populations, and funding for antiretroviral drugs for african countries to reduce maternal-fetal transmission of hiv and to provide care for the large numbers of cases of aids devastating many countries of sub-saharan africa. rotary international has played a key role in polio eradication efforts globally. the public-private consortium global alliance for vaccines and immunization (gavi) has been instrumental in promoting immunization in recent years, with participation by the who, unicef, the world bank, the gates foundation, vaccine manufacturers, and others. this has had an important impact on extending immunization to protect and save the lives of millions of children in deprived countries not yet able to provide fundamental prevention programs such as immunization at adequate levels. gavi has brought vaccines to low-income countries around the world, such as rotavirus vaccine, pentavalent vaccine in myanmar, and pneumococcal vaccine for children in countries in sub-saharan africa, including dr congo. the bill & melinda gates foundation pledged us $ million in to establish gavi, with us $ million per year and us $ billion in to promote the decade of vaccines. international conferences help to create a worldwide climate of advocacy for health issues. international sanitary conferences in the nineteenth century were convened in response to the cholera epidemics. international conferences continue in the twenty-first century to serve as venues for advocacy on a global scale, bringing forward issues in public health that are beyond the scope of individual nations. the who, unicef, and other international organizations perform this role on a continuing basis (see chapter ). criticisms of this approach have focused on the lack of similar effort or donors to address ncds, weak public health infrastructure, and that this frees national governments from responsibility to care for their own children. no one can question, however, that this kind of endeavor has saved countless lives and needs the backing of other aid donors and national government participation. consumerism is a movement that promotes the interests of the purchaser of goods or services. in the s, a new form of consumer advocacy emerged from the civil rights and antiwar movement in the usa. concern was focused on the environment, occupational health, and the rights of the consumer. rachel carson stimulated concern by dramatizing the effects of ddt on wildlife and the environment but inadvertently jeopardized anti-malarial efforts in many countries. this period gave rise to environmental advocacy efforts worldwide, and a political movement, the greens, in western europe. ralph nader showed the power of the advocate or "whistle-blower" who publicizes health hazards to stimulate active public debate on a host of issues related to the public well-being. nader, a consumer advocate lawyer, developed a strategy for fighting against business and government activities and products which endangered public health and safety. his book unsafe at any speed took issue with the us automobile industry for emphasizing profit and style over safety, and led to the enactment of the national traffic and motor safety act of , establishing safety standards for new cars. this was followed by a series of enactments including design and emission standards and seat-belt regulations. nader's work continues to promote consumer interests in a wide variety of fields, including the meat and poultry industries, and coal mining, and promotes greater government regulatory powers regarding pesticide usage, food additives, consumer protection laws, rights to knowledge of contents, and safety standards. consumerism has become an integral part of free market economies, and the educated consumer does influence the quality, content, and price of products. greater awareness of nutrition in health has influenced food manufacturers to improve packaging, content labeling, enrichment with vitamins and minerals, and advertisement to promote those values. low-fat dietary products are available because of an increasingly sophisticated public concerned over dietary factors in cardiovascular diseases. the same process occurred in safe toys and clothing for children, automobile safety features such as mandatory use of car seats for infants, and other innovations that quickly became industry standards in the industrialized world. dangerous practices such as the use of lead paint in toys and melamine contamination of milk products from china capture the public attention quickly and remind public health authorities of the importance of continuous alertness to potential hazards. consumerism can also be exploited by pharmaceutical companies with negative impacts on the health system, especially in the advertising of health products which leads to unnecessary visits to health providers and pressure for approval to obtain the product. the internet has provided people with access to a vast array of information and opinion, and to current literature otherwise unavailable because of the often inadequate library resources of medical and other health professionals. the very freedom of information the internet allows, however, also provides a vehicle for extremist and fringe groups to promote disinformation such as "vaccination causes autism, fluoridation causes cancer", which can cause considerable difficulties for basic public health programs or lead to self-diagnosis of conditions, with often disastrous consequences. advocacy and voluntarism go hand in hand. voluntarism takes many forms, including raising funds for the development of services or operating services needed in the community. it may take the form of fund-raising to build clinics or hospitals in the community, or to provide medical equipment for elderly or handicapped people; or retirees and teenagers working as hospital volunteers to provide services that are not available through paid staff, and to provide a sense of community caring for the sick in the best traditions of religious or municipal concerns. this can also be extended to prevention, as in support for immunization programs, assistance for the handicapped and elderly in transportation, meals-on-wheels, and many other services that may not be included in the "basket of services" provided by the state, health insurance, or public health services. community involvement can take many forms, and so can voluntarism. the pioneering role of women's organizations in promoting literacy, health services, and nutrition in north america during the latter part of the nineteenth and the early twentieth centuries profoundly affected the health of the population. the advocacy function is enhanced when an organization mobilizes voluntary activity and funds to promote changes or needed services, sometimes forcing official health agencies or insurance systems to revise their attitudes and programs to meet these needs. by the early s, canada's system of federally supported provincial health insurance plans covered all of the country. the federal minister of health, marc lalonde, initiated a review of the national health situation, in view of concern over the rapidly increasing costs of health care. this led to articulation of the "health field concept" in , which defined health as a result of four major factors: human biology, environment, behavior, and health care organization (box . ). lifestyle and environmental factors were seen as important contributors to the morbidity and mortality in modern societies. this concept gained wide acceptance, promoting new initiatives that emphasized health promotion in response to environmental and lifestyle factors. conversely, reliance primarily on medical care to solve all health problems could be counterproductive. this concept was a fundamental contributor to the idea of health promotion later articulated in the ottawa declaration, discussed below. the health field concept came at a time when many epidemiological studies were identifying risk factors for cardiovascular diseases and cancers that related to personal habits, such as diet, exercise, and smoking. the concept advocated that public policy needed to address individual lifestyle as part of the overall effort to improve health status. as a result, the canadian federal government established health promotion as a new activity. this quickly spread to many other jurisdictions and gained wide acceptance in many industrialized countries. concern was expressed that this concept could become a justification for a "blame the victim" approach, in which those ill with a disease related to personal lifestyles, such as smokers or aids patients, are seen as having chosen to contract the disease. such a patient might then be considered not to be entitled to all benefits of insurance or care that others may receive. the result may be a restrictive approach to care and treatment that would be unethical in the public health tradition and probably illegal in western jurisprudence. this concept was also used to justify withdrawal from federal commitments in cost sharing and escape from facing controversial health reform in the national health insurance program. during the s and s, outspoken critics of health care systems, such as ivan illytch, questioned the value of medical care for the health of the public. this became a widely discussed, somewhat nihilistic, view towards medical care, and was influential in promoting skepticism regarding the value of the biomedical mode of health care, and antagonism towards the medical profession. in , thomas mckeown presented a historicalepidemiological analysis showing that up to the s, medical care had only a limited impact on mortality rates, although improvements in surgery and obstetrics were notable. he showed that crude death rates in england averaged about per population from to , declining steeply to per in , per in , and per in , when medical care became truly effective. mckeown concluded that much of the improvement in health status over the past several centuries was due to reduced mortality from infectious diseases. this he related to limitation of family size, increased food supplies, improved nutrition and sanitation, specific preventive and therapeutic measures, and overall gains in quality of life for growing elements of the population. he cautioned against placing excessive reliance for health on medical care, much of which was of unproved effectiveness. this skepticism of the biomedical model of health care was part of wider antiestablishment feelings of the s and s in north america. in , milton roemer pointed out that the advent of vaccines, antibiotics, antihypertensives, and other medications contributed to great improvements in infant and child care, and in the management of infectious diseases, hypertension, diabetes, and other conditions. therapeutic gains continue to arrive from teaching centers around the world. vaccine, pharmaceutical, and diagnostic equipment manufacturers continue to provide important innovations that have major benefits, but also raise the cost of health care. the latter issue is one which has stimulated the search for reforms, and search for lower cost technologies such as in treatment of hepatitis c patients, a huge international public health issue. the value of medical care to public health and vice versa has not always been clear, either to public health personnel or to clinicians. the achievements of modern public health in controlling infectious diseases, and even more so in reducing the mortality and morbidity associated with chronic diseases such as stroke and chd, were in reality a shared achievement between clinical medicine and public health (see chapter ). preventive medicine has become part of all medical practice, with disease prevention through early diagnosis and health promotion through individual and community-focused activities. risk factor evaluation determines appropriate screening and individual and community-based interventions. medical care is crucial in controlling hypertension and in reducing the complications and mortality from chd. new modalities of treatment are reducing death rates from first time acute myocardial infarctions. better management of diabetes prevents the early onset of complications. at the same time, the contribution of public health to improving outcomes of medical care is equally important. control of the vaccine-preventable diseases, improved nutrition, and preparation for motherhood contribute to improved maternal and infant outcomes. promotions of reduced exposure to risk factors for chronic disease are a task shared by public health and clinical medical services. both clinical medicine and public health contribute to improved health status. they are interdependent and rely on funding systems for recognition as part of the new public health. during the s, many new management concepts emerged in the business community, such as "management by objective", a concept developed by peter drucker at general motors, with variants such as "zero-based budgeting" developed in the us department of defense (see chapter ). they focused the activities of an organization and its budget on targets, rather than on previous allocation of resources. these concepts were applied in other spheres, but they influenced thinking in health, whose professionals were seeking new ways to approach health planning. the logical application was to define health targets and to promote the efficient use of resources to achieve those targets. this occurred in the usa and soon afterwards in the who european region. in both cases, a wide-scale process of discussion and consensus building was used before reaching definitive targets. this process contributed to the adoption of the targets by many countries in europe as well as by states and many professional and consumer organizations. the usa developed national health objectives in for the year and subsequently for the year , with monitoring of progress in their achievement and development of further targets for and now for . beginning in , state health profiles are prepared by the epidemiology program office of the centers for disease control and prevention based on health indicators recommended by a consensus panel representing public health associations and organizations. the eight mdgs adopted by the un in include halving extreme poverty, reducing child mortality by twothirds, improving maternal health, halting the spread of hiv/aids, malaria, and other diseases, and providing universal primary education, all by the target date of . the mdgs form a common blueprint agreed to by all countries and the world's leading development institutions. the process has galvanized unprecedented efforts to meet the needs of the world's poorest, yet reviews of progress indicate that most developing nations will not meet the targets at current rates of progress. the united nations development programme (undp) global partnership for development report on the mdgs states that if the national development strategies and initiatives are supported by international development partners, the goals can be achieved by . the mdgs were adopted by over nations and provided guidance for national policies and for international aid agencies. the focus was on middle-and low-income countries and their achievements have been considerable but variable (see box . and chapter ) . as of july , extreme poverty was falling in every region, the poverty reduction target had been met, the world had met the target of halving the proportion of people without access to improved sources of water, and the world had achieved parity in primary education between girls and boys. further progress will require sustained political commitment to develop the primary care infrastructure: improved reporting and epidemiological monitoring, consultative mechanisms, and consensus by international agencies, national governments, and non-governmental agencies. the achievement of the targets will also require sustained international support and national commitment with all the difficulties of a time of economic recession. nevertheless, defining a target is crucial to the process. there are encouraging signs that national governments are influenced by the general movement to place greater emphasis on resource allocation and planning on primary care to achieve internationally recognized goals and targets. the successful elimination of smallpox, rising immunization coverage in the developing countries, and increasing implementation of salt iodization have shown that such goals are achievable. while the usa has not succeeded in developing universal health care access, it has a strong tradition of public health and health advocacy. federal, state, and local health authorities have worked out cooperative arrangements for financing and supervising public health and other services. with growing recognition in the s that medical services alone would not achieve better health results, health policy leadership in the federal government formulated a new approach, in the form of developing specific health targets for the nation. in , the surgeon general of the usa published the report on health promotion and disease prevention (healthy people). this document set five overall health goals for each of the major age groups for the year , accompanied by specific health objectives. new targets for the year were developed in three broad areas: to increase healthy lifespans, to reduce health disparities, and to achieve access to preventive health care for all americans. these broad goals are supported by specific targets in health priority areas, each one divided into four major categories: health promotion, health protection, preventive services, and surveillance systems. this set the public health agenda on the basis of measurable indicators that can be assessed year by year. reduce child mortality -progress on child mortality is gaining momentum. the target is to reduce by two-thirds, between and , the under- -year-old mortality rate, from children of every dying to of every . child deaths are falling, but much more needs to be done in order to reach the development goal. revitalizing efforts against pneumonia and diarrhea, while bolstering nutrition, could save millions of children. l mdg . improve maternal health -maternal mortality has nearly halved since , but levels are far removed from the target. the targets for improving maternal health include reducing by three-quarters the maternal mortality ratio and achieve universal access to reproductive health. poverty and lack of education perpetuate high adolescent birth rates. inadequate funding for family planning is a major failure in fulfilling commitments to improving women's reproductive health. l mdg . combat hiv/aids, malaria, tuberculosis, and other diseases -more people than ever are living with hiv owing to fewer aids-related deaths and the continued large number of new infections. in , an estimated . million were living with hiv, up percent from . this persistent increase reflects the continued large number of new infections along with a significant expansion of access to lifesaving antiretroviral therapy, especially in more recent years. l mdg . ensure environmental sustainability -the unparalleled success of the montreal protocol shows that action on climate change is within grasp. the th anniversary of the montreal protocol on substances that deplete the ozone layer, in , had many achievements to celebrate. most notably, there has been a reduction of over percent in the consumption of ozone-depleting substances. further, because most of these substances are also potent greenhouse gases, the montreal protocol has contributed significantly to the protection of the global climate system. the reductions achieved to date leave hydrochlorofluorocarbons (hcfcs) as the largest group of substances remaining to be phased out. l mdg . a global partnership for development -core development aid fell in real terms for the first time in more than a decade, as donor countries faced fiscal constraints. in , net aid disbursements amounted to $ . billion, representing . percent of developed countries' combined national income. while constituting an increase in absolute dollars, this was a . percent drop in real terms over . if debt relief and humanitarian aid are excluded, bilateral aid for development programmes and projects fell by . percent in real terms. equitable and sustainable funding of health services. . developing human resources (educational programs for providers and managers based on the principles of the health for all policy). . research and knowledge: health programs based on scientific evidence. . mobilizing partners for health (engaging the media/ television/internet). . policies and strategies for health for all -national, targeted policies based on health for all. a - review has been commissioned by the european office of the who to assess inequalities in the social determinants of health. while health has improved there are still significant inequalities. factors include variance in local, regional, national, and global economic forces. the european union and the european region of who are both working on health targets for the year . there are competing demands in society for expenditure by the government, and therefore making the best use of resources -money and people -is an important objective. the uk has devolved many of the responsibilities to the constituent countries (england, wales, scotland, and northern ireland) within an overall national framework (box . ). of the health consequences of their decisions and to accept responsibility for health. health promotion policy combines diverse but complementary approaches, including legislation, fiscal measures, taxation, and organizational change. it is a coordinated action that leads to health, income, and social policies that foster greater equity. joint action contributes to ensuring safer and healthier goods and services, healthier public services, and cleaner, more enjoyable environments. health promotion policies require the identification of obstacles to the adoption of healthy public policies in non-health sectors, and ways of removing them. built on progress made from the declaration on primary health care at alma-ata, the aim was to make the healthier choice the easier choice for policy makers as well. the logo of the ottawa charter has been maintained by the who as the symbol and logo of health promotion. health promotion represents activities to enhance and embed the concept of building healthy public policy through: l building healthy public policy in all sectors and levels of government and society l enhancing both self help and social support l developing personal skills through information and education for health l enabling, mediating, and advocating healthy public policy in all spheres l creating supportive environments of mutual help and conservation of the natural environment l reorienting health services beyond providing clinical curative services with linkage to broader social, political, economic, and physical environmental components. (adapted from ottawa charter; health and welfare canada and world health organization, ) an effective approach to health promotion was developed in australia where, in the state of victoria, revenue from a cigarette tax has been set aside for health promotion purposes. this has the effect of discouraging smoking, and at the same time finances health promotion activities and provides a focus for health advocacy in terms of promoting cessation of cigarette advertising at sports events or on television. it also allows for assistance to community groups and local authorities to develop health promotion activities at the workplace, in schools, and at places of recreation. health activity in the workplace involves reduction of work hazards as well as promotion of a healthy diet and physical fitness, and avoidance of risk factors such as smoking and alcohol abuse. in the australian model, health promotion is not only the persuasion of people to change their life habits; it also involves legislation and enforcement towards environmental changes that promote health. for example, this involves mandatory filtration, chlorination, and fluoridation for community water supplies, vitamin and mineral enrichment of basic foods. primary care alliances of service providers are organized including hospitals, community health services serving a sub-district population for more efficient and comprehensive care. these are at the level of national or state policy, and are vital to a health promotion program and local community action. community-based programs to reduce chronic disease using the concept of community-wide health promotion have developed in a wide variety of settings. such a program to reduce risk factors for cardiovascular disease was pioneered in the north karelia project in finland. this project was initiated as a result of pressures from the affected population of the province, which was aware of the high incidence of mortality from heart disease. finland had the highest rates of chd in the world and in the rural area of north karelia the rate was even higher than the national average. the project was a regional effort involving all levels of society, including official and voluntary organizations, to try to reduce risk factors for chd. after years of follow-up, there was a substantial decline in mortality with a similar decline in a neighboring province taken for comparison, although the decline began earlier in north karelia. in many areas where health promotion has been attempted as a strategy, community-wide activity has developed with participation of ngos or any valid community group as initiators or participants. healthy heart programs have developed widely with health fairs, sponsored by charitable or fraternal societies, schools, or church groups, to provide a focus for leadership in program development. a wider approach to addressing health problems in the community has developed into an international movement of "healthy cities". following deliberations of the health of towns commission chaired by edwin chadwick, the health of towns association was founded in by southwood smith, a prominent reform leader of the sanitary movement, to advocate change to reduce the terrible living conditions of much of the population of cities in the uk. the association established branches in many cities and promoted sanitary legislation and public awareness of the "sanitary idea" that overcrowding, inadequate sanitation, and absence of safe water and food created the conditions under which epidemic disease could thrive. in the s, iona kickbush, trevor hancock, and others promoted renewal of the idea that local authorities have a responsibility to build health issues into their planning and development processes. this "healthy cities" approach promotes urban community action on a broad front of health promotion issues (table . ). activities include environmental projects (such as recycling of waste products), improved recreational facilities for young people to reduce violence and drug abuse, health fairs to promote health awareness, and screening programs for hypertension, breast cancer, and other diseases. it combines health promotion with consumerism and returns to the tradition of local public health action and advocacy. the municipality, in conjunction with many ngos, develops a consultative process and program development approach to improving the physical and social life of the urban environment and the health of the population. in , the healthy cities movement involved countries with cities in europe, canada, the usa, the uk, south america, israel, and australia, an increase from cities in . the model now extends to small municipalities, often with populations of fewer than , . networks of healthy cities are the backbone of the movement, with more than member towns and cities across europe. the choice of core themes offers the opportunity to work on priority urban health issues that are relevant to all european cities. topics that are of particular concern to individual cities and/or are challenging and cutting edge for innovative public health action are especially emphasized. healthy cities encourages and supports experimentation with new ideas by developing concepts and implementing them in diverse organizational contexts. a healthy city is a city for all its citizens: inclusive, supportive, sensitive and responsive to their diverse needs and expectations. a healthy city provides conditions and opportunities that encourage, enable and support healthy lifestyles for people of all social groups and ages. a healthy city offers a physical and built environment that encourages, enables and supports health, recreation and well-being, safety, social interaction, accessibility and mobility, a sense of pride and cultural identity and is responsive to the needs of all its citizens. the apha's formulation of the public health role in , entitled the future of public health in america, was presented at the annual meeting in . the apha periodically revises standards and guidelines for organized public health services provided by federal, state, and local governments ( table . ). these reflect the profession of public health as envisioned in the usa where access to medical care is limited for large numbers of the population because of a lack of universal health insurance. public health in the usa has been very innovative in determining risk groups in need of special care and finding direct and indirect methods of meeting those needs. european countries such as finland have called for setting public health into all public policy, which reflects the vital role that local and county governments can play in developing health-oriented policies. these include policies in housing, recreation, regulation of industrial pollution, road safety, promotion of smoke-free environments, bicycle paths, health impact assessment, and many other applications of health principles in public policy. public health involves both direct and indirect approaches. direct measures in public health include immunization of children, modern birth control, and chronic disease case finding -hypertension, diabetes, and cancer. indirect methods used in public health protect the individual by community-wide means, such as raising standards of environmental safety, ensuring a safe water supply, sewage disposal, and improved nutrition (box . ). in public health practice, the direct and indirect pproaches are both relevant. to reduce morbidity and mortality from diarrheal diseases requires an adequate supply of safe water and waste disposal, and also education of the individual in hygiene and the mother in use of ort, and rotavirus vaccination of all children. the targets of public health action therefore include the individual, family, community, region, or nation, as well as a functioning and health system adopting current best practices for health care and health protection. the targets for protection in infectious disease control are both the individual and the total group at risk. for vaccine-preventable diseases, immunization protects the individual but also has an indirect effect by reducing the risk even for non-immunized persons. in control of some diseases, individual case finding and management reduce risk of the disease in others and the community. for example, tb requires case finding and adequate care among high-risk groups as a key to community control. in malaria control, case finding and treatment are essential together with environmental action to reduce the vector population, to prevent transmission of the organism by the mosquito to a new host. control of ncds, where there is no vaccine for mass application, depends on the knowledge, attitudes, beliefs, and practices of individuals at risk. in this case, the social context is of importance, as is the quality of care to which the individual has access. control and prevention of noninfectious diseases involve strategies using individual and population-based methods. individual or clinical measures include professional advice on how best to reduce the risk of the disease by early diagnosis and implementation of appropriate therapy. population-based measures involve indirect measures with government action banning cigarette advertising, or direct taxation on cigarettes. mandating food quality standards, such as limiting the fat content of meat, and requiring food labeling laws are part of the control of cardiovascular diseases. the way individuals act is central to the objective of reducing disease, because many non-infectious diseases are dependent on behavioral risk factors of the individual's choosing. changing the behavior of the individual means addressing the way a person sees his or her own needs. this can be influenced by the provision of information, but how someone sees his or her own needs is more complex than that. an individual may define needs differently from the society or the health system. reducing smoking among women may be difficult to achieve if smoking is thought to reduce appetite and food intake, given the social message that "slim is beautiful". reducing smoking among young people is similarly difficult if smoking is seen as fashionable and diseases such as lung cancer seem very remote. recognizing how individuals define needs helps the health system to design programs that influence behavior that is associated with disease. public health has become linked to wider issues as health care systems are reformed to take on both individual and population-based approaches. public health and mainstream medicine have found increasingly common ground in addressing the issues of chronic disease, growing attention to health promotion, and economics-driven health care reform. at the same time, the social ecology approaches have shown success in slowing major causes of disease, including heart disease and aids, and the biomedical sciences have provided major new technology for preventing major health problems, including cancer, heart disease, genetic disorders, and infectious diseases. technological innovations unheard of just a few years ago are now commonplace, in some cases driving up costs of care and in others replacing older and less effective care. at the same time, resistance of important pathogenic microorganisms to antibiotics and pesticides is producing new challenges from diseases once thought to be under control, and newly emerging infectious diseases challenge the entire health community. new generations of antibiotics, antidepressants, antihypertensive medications, and other treatment methods are changing the way many conditions are treated. research and development in the biomedical to improve the quality of public health practice and performance of public health systems sciences are providing means of prevention and treatment that profoundly affect disease patterns where they are effectively applied. the technological and organizational revolutions in health care are accompanied by many ethical, economic, and legal dilemmas. the choices in health care include heart transplantation, an expensive life-saving procedure, which may compete with provision of funds and labor resources for immunizations for poor children or for health promotion to reduce smoking and other risk factors for chronic disease. new means of detecting and treating acute conditions such as myocardial infarction and peptic ulcers are reducing hospital stays, and improving long-term survival and quality of life. imaging technology has been an important development in medicine since the advent of x-rays in the early twentieth century. technology has forged ahead with high-technology instruments and procedures, new medication, genetic engineering, and important low-technology gains such as impregnated bed nets, simplified tests for hiv and tb, and many other "game changers". new technologies that can enable lower cost diagnostic devices, electronic transmission, and distant reading of transmitted imaging all open up possibilities for advanced diagnostic capacities in rural and less developed countries and communities. molecular biology has provided methods of identifying and tracking movement of viruses such as polio and measles from place to place, greatly expanding the potential for appropriate intervention. the choices in resource allocation can be difficult. in part, these add political commitment to improve health, competent professionally trained public health personnel, the public's level of health information, and legal protection, whether through individuals, advocacy, or regulatory approaches for patients' rights. these are factors in a widening methodology of public health. the centers for disease control and prevention (morbidity and mortality weekly report) in summarized great achievements of public health in the usa, with an extension of the lifespan by over years and improvements in many measures of quality of life. they were updated in a similar summary report in , showing continuous progress, and a global version which was also encouraging in its scope of progress (table . ). these achievements were also seen in all developed countries over the past century and are beginning to be seen in developing countries as well. they reflect a successful application of a broad approach to prevention and health promotion along with improved medical care and growing access to its benefits. in the past several decades alone, major new innovations are leading to greater control of cardiovascular disease, cancer prevention, and many other improvements to health affecting hundreds of millions of people. a similar report by the cdc shows global progress in the first decade of the twenty-first century, while mdg reports show progress on all eight target topics, although not at uniformly satisfactory rates. these achievements are discussed throughout this text. this successful track record is very much at the center of a new public health involving a wide range of programs and activities, shown to be feasible and benefiting from continuing advances in science and understanding of social and management issues affecting health care systems worldwide. public health issues have received new recognition in recent years because of a number of factors, including a growing understanding among the populace at different levels in different countries that health behavior is a factor in health status and that public health is vital for protection against natural or human-made disasters. the challenges are also increasingly understood: preparation for bioterrorism, avian influenza, rising rates of diabetes and obesity, high mortality rates from cancer, and a wish for prevention to be effective. health systems offer general population benefits that go beyond preventing and treating illness. appropriately designed and managed, they: l provide a vehicle to improve people's lives, protecting them from the vulnerability of sickness, generating a sense of life security, and building common purpose within society l ensure that all population groups are included in the processes and benefits of socioeconomic development l generate the political support needed to sustain them over time. health systems promote health equity when their design and management specifically consider the circumstances and needs of socially disadvantaged and marginalized populations, including women, the poor, and groups who experience stigma and discrimination, enabling social action by these groups and the civil society organizations supporting them. health systems can, when appropriately designed and managed, contribute to achieving the millennium development goals. the mdgs selected by the un in have eight global targets for the year , including four directly related to public health (discussed above, box . ). these are a recognition and a challenge to the international community and public health as a profession and as organized systems. formal education in newly developing schools of public health is increasing in europe, including many countries of eastern europe, and beginning to develop in india and sub-saharan africa. but there is delay in establishing centers of postgraduate education and research in many developing countries which are concentrating their educational resources on training physicians. many physicians from developing nations are moving to the developed countries, which have become dependent on these countries for a significant part of their supply of medical doctors. progress in implementation of the mdgs is mixed in sub-saharan africa, making some progress in immunization, but falling back on other goals. proposals to renew global health targets following the end-stage of the mdg health goals will need to add a focus on ncds, which account for percent of global deaths, including . million premature deaths below the age of (undp). economic growth has been hampered by the global recession since , which will affect continued progress with many other factors of changing population dynamics, the economics of prevention versus expensive treatment costs, and the high costs of health care. environmental degradation with high levels of carbon dioxide contamination is a growing concern, with disastrous global warming and consequent effects of drought, flooding, hurricane, and elevated particulate matter-induced asthma and effects on cardiovascular disease. the potential for the development of basic and medical sciences in genetics, nanotechnology, and molecular biology shows enormous promise for health benefits as yet unimagined. at the same time, the effectiveness of health promotion has shown dramatic successes in reducing the toll of aids, reducing smoking, and increasing consciousness of nutrition and physical fitness in the population, and of the tragic effects of poverty and poor education on health status. the ethics of public health issues are complex and changing with awareness that failure to act on strong evidence-based policies is itself ethically problematic. the future of public health is not as a solo professional sector; it is at the heart of health systems, without which societies are open to chronic and infectious diseases that are preventable, affecting the society as a whole in economic and development matters. there is an expanding role of private donors in global health efforts, such as the rotary club and the polio eradication program, gavi with immunization and bed-nets in sub-saharan africa, and bilateral donor countries' help in reducing the toll of aids in sub-saharan africa. the new public health has emerged as a concept to meet a whole new set of conditions, associated with increasing longevity and aging of the population, with the post-world war ii baby-boom generation reaching the over- age group facing the growing importance of chronic diseases. inequalities in health exist in and between affluent and developing societies, as well as within countries, even those having advanced health care systems. regional inequalities are seen across the european region in an east-west gradient and globally a north-south divide of extremes of inequality. the global environmental and ecological degradation and pollution of air and water present grave challenges for developed and developing countries worldwide. yet optimism can be derived from proven track records of success in public health measures that have already been implemented. many of the underlying factors are amenable to prevention through social, environmental, or behavioral change and effective use of medical care. the new public health idea has evolved since alma-ata, which articulated the concept of health for all, followed by a trend in the late s to health in all policies and establishing health targets as a basis for health planning. during the late s and early s, the debate on the future of public health in the americas intensified as health professionals looked for new models and approaches to public health research, training, and practice. this debate helped to redefine traditional approaches of social, community, and preventive medicine. the search for the "new" in public health continued with a return to the health for all concept of alma-ata (renewed in ) and a growing realization that the health of both the individual and the society involves the management of personal care services and community prevention, with a comprehensive approach taking advantage of advancing technology and experience of best practices globally. the new public health is an extension of the traditional public health. it describes organized efforts of society to develop healthy public policies: to promote health, to prevent disease, and to foster social equity within a framework of sustainable development. a new, revitalized public health must continue to fulfill the traditional functions of sanitation, protection, and related regulatory activities, but in addition to its expanded functions. it is a widened philosophy and practical application of many different methods of addressing health, and preventing disease and avoidable death. it necessarily addresses inequities so that programs need to meet special needs of different groups in the population according to best standards, limited resources, and population needs. it is proactive and advocates interventions within legal and ethical limits to promote health as a value in and of itself and as an economic gain for society as well for its individual members. the new public health is a comprehensive approach to protecting and promoting the health status of the individual and the society, based on a balance of sanitary, environmental, health promotion, personal, and community-oriented preventive services, coordinated with a wide range of curative, rehabilitative, and long-term care services. it evolves with new science, technology, and knowledge of human and systems behavior to maximize health gains for the individual and the population. the new public health requires an organized context of national, regional, and local governmental and non-governmental programs with the object of creating healthful social, nutritional, and physical environmental conditions. the content, quality, organization, and management of component services and programs are all vital to its successful implementation. whether managed in a diffused or centralized structure, the new public health requires a systems approach acting towards achievement of defined objectives and specified targets. the new public health works through many channels to promote better health. these include all levels of government and parallel ministries; groups promoting advocacy, academic, professional, and consumer interests; private and public enterprises; insurance, pharmaceutical, and medical products industries; the farming and food industries; media, entertainment, and sports industries; legislative and law enforcement agencies; and others. the new public health is based on responsibility and accountability for defined populations in which financial systems promote achievement of these targets through effective and efficient management, and cost-effective use of financial, human, and other resources. it requires continuous monitoring of epidemiological, economic, and social aspects of health status as an integral part of the process of management, evaluation, and planning for improved health. the new public health provides a framework for industrialized and developing countries, as well as countries in political-economic transition such as those of the former soviet system. they are at different stages of economic, epidemiological, and sociopolitical development, each attempting to ensure adequate health for its population with limited resources. the challenges are many, and affect all countries with differing balances, but there is a common need to seek better survival and quality of life for their citizens (table . ). the object of public health, like that of clinical medicine, is better health for the individual and for society. public health works to achieve this through indirect methods, such as by improving the environment, or through direct means such as preventive care for mothers and infants or other atrisk groups. clinical care focuses directly on the individual patient, mostly at the time of illness. but the health of the individual depends on the health promotion and social programs of the society, just as the well-being of a society depends on the health of its citizens. the new public health consists of a wide range of programs and activities that link individual and societal health. the "old" public health was concerned largely with the consequences of unhealthy settlements and with safety of food, air, and water. it also targeted the infectious, toxic, and traumatic causes of death, which predominated among young people and were associated with poverty. a summary of the great achievements of public health in the twentieth and in the early twenty-first century in the industrialized world is included in chapter and throughout this text. these achievements are reflective of public health gains throughout the industrialized world and are encourage and leverage national, state, and local partnerships to build a stronger foundation for public health preparedness and investigate health problems and health hazards in the community . inform, educate, and empower people about health issues . mobilize community partnerships to identify and solve health problems . develop policies and plans that support individual and community health efforts . enforce laws and regulations that protect health and ensure safety evaluate effectiveness, accessibility, and quality of personal and population-based health services vision, mission and goals guidelines on food fortification with micronutrients. who, geneva. alliance for health policy and systems research essential public health services healthy communities, . model standards for community attainment of the year national health objectives determinants of adult mortality in russia: estimates from sibling data commission on social determinants and health. closing the gap in a generation: health equity through action on the social determinants of health compression of morbidity in the elderly institute of medicine. who will keep the public healthy? educating public health professionals for the st century global alliance for vaccine and immunization (gavi) chronic disease prevention and the new public health the evolution, impact and significance of healthy cities/healthy communities world health organization. ottawa charter for health promotion: an international conference on health promotion behavioral and social sciences and public health at cdc. mmwr health in all policies: seizing opportunities, implementing policies. ministry of social affairs and health new perspectives on the health of canadians: a working document new perspective on the health of canadians: years later the us healthy people initiative: its genesis and its sustainability mortality from cardiovascular and cerebrovascular diseases in europe and other areas of the world: an update strategic review of health inequalities in england post. department of health primary care (extended version): ten key actions could globally ensure a basic human right at almost unnoticeable cost public health in europe: power, politics, and where next health: a vital investment for economic development in eastern europe and central asia. european observatory on health systems and policies. who, european regional office it is not just the broad street pump addressing the epidemiologic transition in the former soviet union: strategies for health systems and public health reform in russia what is the "new public health"? millenium development goals: progress chart united nations development programme, millennium development goals. eight goals for healthy people healthy people. the surgeon general's report on health promotion and disease prevention the millennium development goals: a cross-sectoral analysis and principles for goal-setting after selective primary health care: an interim strategy for disease control in developing countries declaration of alma-ata. international conference on primary health care healthy cities networks across the who, european region preamble to the constitution of the world health organization as adopted by the international health conference regional office for europe. health -health for all in the st century. who regional office for europe, copenhagen. world health organization, . regional office for europe. who european healthy cities network. available at:. who regional office for europe leading health indicators selected for incorporate the original objectives in healthy people , which served as a basis for planning public health activities for many state and community health initiatives. for each of the leading health indicators, specific objectives and subobjectives derived from healthy people are used to monitor progress. the specific objectives set for healthy people are listed in box . . thirteen new topic areas are listed for , such as older adults, genomics, dementias, and social determinants of health. these provide guidelines for national, state, and local public health agencies as well as insurance providers, primary care services, and health promotion advocates. a key issue will be in reducing regional, ethnic, and socioeconomic health disparities.the process of working towards health targets in the usa has moved down from the federal level of government to the state and local levels. professional organizations, ngos, as well as community and fraternal organizations are also involved. the states are encouraged to prepare their own targets and implementation plans as a condition for federal grants, and many states require county health departments to prepare local profiles and targets.diffusion of this approach encourages state and local initiatives to meet measurable program targets. it also sets a different agenda for local prestige in competitive terms, with less emphasis on the size of the local hospital or other agencies than on having the lowest infant mortality or the least infectious disease among neighboring local authorities. the who european region document "health -health for all in the st century" addresses health in the twentyfirst century, with principles and objectives for improving the health of europeans, within and between countries of europe. the health targets include: . closing the health gap between countries. . closing the health gap within countries. . a healthy start in life (supportive family policies). . health of young people (policies to reduce child abuse, accidents, drug use, and unwanted pregnancies). . healthy aging (policies to improve health, self-esteem, and independence before dependence emerges). . improving mental health. . reducing communicable diseases. . reducing non-communicable diseases. . reducing injury from violence and accidents. . a healthy and safe physical environment. . healthier living (fiscal, agricultural, and retail policies that increase the availability of and access to and consumption of vegetables and fruits). . reducing harm from alcohol, drugs, and tobacco. . a settings approach to health action (homes should be designed and built in a manner conducive to sustainable health and the environment). . multisectoral responsibility for health. . an integrated health sector and much stronger emphasis on primary care. . managing for quality of care using the european health for all indicators to focus on outcomes and compare the effectiveness of different inputs. the uk national health service (nhs) has semi-autonomous units in england, scotland, wales, and northern ireland. they are funded from the central uk nhs but with autonomy within national guidelines. the nhs has defined national health outcomes for improvements grouped around five domains, each comprised of key indicators aimed at improving health with reducing inequalities. l preventing people from dying prematurely from causes amenable to health care for all ages: l the target diseases include cardiovascular, respiratory, and liver diseases, and cancer (with focus on cancer of breast, lung, and colorectal cancer) l reducing premature death in people with serious mental illnesses l reducing infant mortality, neonatal mortality, still births, and deaths in young children l increasing -year survival for children with cancer. health improvement; help people to live healthy lifestyles, healthy choices, reduce health inequalities, protection from major incidents and other threats, while reducing health inequalities. l health care, public health and preventing premature mortality; reduce the numbers of people living with preventable ill-health and people dying prematurely, while reducing the gap between communities.source: uk department of health. available at: https://www.gov.uk/government/organisations/department-of-health/about#our-priorities, https:// www.gov.uk/government/uploads/system/uploads/attachment_data/ file/ /improving-outcomes-and -supporting-transparency-part- a.pdf. pdf, and https://www.gov.uk/government/uploads/system/uploads/attach-ment_data/file/ / -nhs-outcomes-framework- - .pdf. pdf [accessed june ] . national policy in health ultimately relates to health of the individual. the various concepts outlined in the health field concept, community-oriented primary health care, health targets, and effective management of health systems, can only be effective if the individual and his or her community are knowledgeable participants in seeking solutions. involving the individual in his or her own health status requires raising levels of awareness, knowledge, and action. the methods used to achieve these goals include health counseling, health education, and health promotion (figure . ).health counseling has always been a part of health care between the doctor or nurse and the patient. it raises levels of awareness of health issues of the individual patient. health education has long been part of public health, dealing with promoting consciousness of health issues in selected target population groups. health promotion incorporates the work of health education but takes health issues to the policy level of government and involves all levels of government and ngos in a more comprehensive approach to a healthier environment and personal lifestyles.health counseling, health education, and health promotion are among the most cost-effective interventions for improving the health of the public. while costs of health care are rising rapidly, demands to control cost increases should lead to greater emphasis on prevention, and adoption of health education and promotion as an integral part of modern life. this should be carried out in schools, the workplace, the community, commercial locations (e.g., shopping centers), and recreation centers, and in the political agenda.psychologist abraham maslow described a hierarchy of needs of human beings. every human has basic requirements including physiological needs of safety, water, food, warmth, and shelter. higher levels of needs include recognition, community, and self-fulfillment. these insights supported observations of efficiency studies such as those of elton mayo in the famous hawthorne effect in the s, showing that workers increased productivity when acknowledged by management in the objectives of the organization (see chapter ). in health terms, these translate into factors that motivate people to positive health activities when all barriers to health care are reduced.modern public health faces the problem of motivating people to change behavior; sometimes this requires legislation, enforcement, and penalties for failure to comply, such as in mandating car seat-belt use. in other circumstances it requires sustained performance by the individual, such as the use of condoms to reduce the risk of sti and/or hiv transmission. over time, this has been developed into a concept known as knowledge, attitudes, beliefs, and practices (kabp), a measurable complex that cumulatively affects health behavior (see chapter ). there is often a divergence between knowledge and practice; for example, the knowledge of the importance of safe driving, yet not putting this into practice. this concept is sometimes referred to as the "kabp gap". the health belief model has been a basis for health education programs, whereby a person's readiness to take action for health stems from a perceived threat of disease, a recognition of susceptibility to disease and its potential severity, and the value of health. action by an individual may be triggered by concern and by knowledge. barriers to appropriate action may be psychological, financial, or physical, including fear, time loss, and inconvenience. spurring action to avoid risk to health is one of the fundamental goals in modern health care. the health belief model is important in defining any health intervention in that it addresses the emotional, intellectual, and other barriers to taking steps to prevent or treat disease.health awareness at the community and individual levels depends on basic education levels. mothers in developing countries with primary or secondary school education are more successful in infant and child care than less educated women. agricultural and health extension services reaching out to poor and uneducated farm families in north america in the s were able to raise consciousness of safe self-health practices and good nutrition, and when this was supplemented by basic health education in schools, generational differences could be seen in levels of awareness of the importance of balanced nutrition. secondary prevention with diabetics and patients with chd hinges on education and awareness of nutritional and physical activity patterns needed to prevent or delay a subsequent myocardial infarction. the who sponsored the first international conference on health promotion held in ottawa, canada, in ( figure . ) . the resulting ottawa charter defined health promotion and set out five key areas of action: building healthy public policy, creating supportive environments, strengthening community action, developing personal skills, and reorienting health services. the ottawa charter called on all countries to put health on the agenda of policy makers in all sectors and at all levels, directing them to be aware a typical healthy city has a population in the multiple thousands, often multilingual, with an average middleclass income. a healthy cities project builds a coalition of municipal and voluntary groups working together in a continuing effort to improve quality of service, facilities, and living environment. the city is divided into neighborhoods, engaged in a wide range of activities fostered by the project. municipalities have traditionally had a leading role in sanitation, safe water supply, building and zoning laws and regulation, and many other responsibilities in public health (see chapter ). the healthy cities or communities movement has elevated this to a higher level with policies to promote health in all actions. some examples are listed of municipal, advocacy group, and higher governmental activities for healthier city environments: working with senior levels of government, other departments in the municipalities, religious organizations, private donors, and the ngo sector to innovate and especially to improve conditions in poverty-afflicted areas of cities is a vital role for health-oriented local political leadership. human ecology, a term introduced in the s and revived in the s, attempted to apply theory from plant and animal life to human communities. it evolved as a branch of demography, sociology, and anthropology, addressing the social and cultural contexts of disease, health risks, and human behavior. human ecology addresses the interaction of humans with and adaptation to their social and physical environment.parallel subdisciplines of social, community, and environmental psychology, medical sociology, anthropology, and other social sciences contributed to the development of this academic field with wide applications in health-related issues. this led to the incorporation of qualitative research methods alongside the quantitative research methods traditionally emphasized in public health, providing crucial insights into many public health issues where human behavior is a key risk factor.health education developed as a discipline and function within public health systems in school health, rural nutrition, military medicine, occupational health, and many other aspects of preventive-oriented health care, and is discussed in later chapters of this text. directed at behavior modification through information and raising awareness of consequences of risk behavior, this has become a longstanding and major element of public health practice in recent times, being almost the only effective tool to fight the epidemic of hiv and the rising epidemic of obesity and diabetes.health promotion as an idea evolved, in part, from marc lalonde's health field concepts and from growing realization in the s that access to medical care was necessary but not sufficient to improve the health of a population. the integration of the health behavior model, social ecological approach, environmental enhancement, or social engineering formed the basis of the social ecology approach to defining and addressing health issues (table . ).individual behavior depends on many surrounding factors, while community health also relies on the individual; the two cannot be isolated from one another. the ecological perspective in health promotion works towards changing people's behavior to enhance health. it takes into account factors not related to individual behavior, which are determined by the political, social, and economic environment. it applies broad community, regional, or national approaches that are needed to address severe public health problems, such as controlling hiv infection, tb, malnutrition, stis, cardiovascular disorders, violence and trauma, and cancer. beginning to affect the health situation in countries in transition from the socialist period. countries emerging from developing status are also showing signs of mixed progress in the dual burden of infectious and maternal/child health issues, along with growing exposure to the chronic diseases of developed nations such as cardiovascular diseases, obesity, and diabetes. the new public health synthesizes traditional pub lic health with management of personal services and community action for a holistic approach. evaluation of costeffective public health and medical interventions to reduce the burden of disease also contributes to the need to seek and apply new approaches to health. the new public health will continue to evolve as a framework drawing on new ideas, science, technology, and experiences in public health throughout the world. it must address the growing recognition of social inequality in health, even in developed countries with universal health programs with improved education and social support systems. for a complete bibliography and guidance for student reviews and expected competencies please see companion web site at http://booksite.elsevier.com/ bibliography key: cord- -nquov i authors: murphy, f.a. title: epidemiology of human and animal viral diseases date: - - journal: encyclopedia of virology doi: . /b - - . - sha: doc_id: cord_uid: nquov i viral disease epidemiology is the study of the determinants, dynamics, and distribution of viral diseases in populations. the risk of infection or disease in a population is determined by characteristics of the virus, the host, and the host population, as well as behavioral, environmental, and ecological factors that affect virus transmission from one host to another. viral disease epidemiology has come to have a major role in clarifying the etiologic role of particular viruses and viral variants as the cause of specific diseases, in improving our understanding of the overall nature of specific viral diseases, and in determining factors affecting host susceptibility and immunity, in unraveling modes of transmission, in clarifying the interaction of viruses with environmental determinants of disease, in determining the safety, efficacy, and utility of vaccines and antiviral drugs, and especially in alerting and directing disease prevention and control actions. information on incidence, prevalence, and morbidity and mortality rates contributes directly to the establishment of priorities for prevention and control programs, whether this involves vaccine or drug development and delivery, environmental and hygienic improvements, enhancement of nutritional status, personal or community behavior, agricultural and food processing enhancements, reservoir host and vector control, and international cooperation and communication. evs, they encode other types of defense molecules. among these are the inhibitor of apoptosis (iap) genes. the iap of amev has been well characterized and functionally inhibits apoptosis. a related amev gene that functions to inhibit apoptosis is a homolog of the baculovirus pan-caspase inhibitor, p . another novel protein expressed by amev is a cu-zn superoxide dismutase (sod) . although a number of the orthopoxviruses encode genes with homology to this class of sods, neither the vv or myxoma virus proteins are functional in that capacity, although they are present within the virion. the sod expressed by amev is functional as an sod but is not essential for virus growth in culture. the deletion of the sod gene from amev appears to have no effect on the growth of the virus in gypsy moth larvae. it is clear that this large subfamily of the family poxviridae provides a wealth of possible information about the basic mechanisms of the poxvirus lifecycle. there appear to be a number of interesting variations on the molecular details which define this overall family of viruses. there are clear similarities to the vertebrate poxviruses in virion morphology, double-stranded dna genome, cytoplasmic life cycle, and rna expression. yet the differences between the cvs and evs are significant and represent an area of research that has not been fully explored. the data that have been obtained from genomic sequencing has been essential to identifying some of the different proteins that are present in the evs, as well as identifying potentially missing homologs of vv proteins. it is important to note that there are large differences at the dna level between the two sequenced evs, indicating that there is probably a wide variety of unique features within the evs as a group. as more sequence information becomes available, the diversity of this family of viruses may become more evident. direct contact transmission involves actual physical contact between an infected subject and a susceptible subject (e.g., kissing, biting, coitus). epidemic major increase in disease incidence affecting either a large number of humans or animals or spreading over a large area. epidemiology the study of the determinants, dynamics, and distribution of diseases in populations. fomite an inanimate object that may be contaminated with virus and become the vehicle for transmission. herd immunity the immune status of a population that affects viral transmission rates. often used in describing the elimination of a virus from a population when there are too few susceptible hosts remaining to sustain a transmission chain. horizontal transmission the transfer of infectious virus from one human or animal to another by any means other than vertical transmission. iatrogenic transmission transmission via health care procedures, materials, and workers (e.g., physicians, nurses, dentists, veterinarians). incidence rate (or attack rate) a measure of the occurrence of infection or disease in a population over time -it refers to the proportion of a population contracting a particular disease during a specified period. mathematical model (epidemiological) a means to convey quantitative information about a host-virus interaction, such as an epidemic or an emerging disease episode, by the construction of a set of predictive mathematical algorithms. nosocomial transmission pertains to infections acquired while a patient, human or animal, is in hospital. prevalence rate the ratio, at a particular point in time, of the number of cases currently present in the population divided by the number of subjects in the population at risk; it is a snapshot of the occurrence of infection or disease at a given time. species jumping (or host range extension) referring to a virus that derives from an ancient reservoir life cycle in animals, but has subsequently established a new life cycle in humans or a different animal species and no longer uses, the original animal reservoir. transmission the process by which a pathogen is shed from one host and infects the next. vector-borne transmission involves the bites of arthropod vectors (e.g., mosquitoes, ticks, sandflies). vertical or transplacental transmission occurs from mother to fetus prior to or during parturition, either across the placenta, when the fetus passes through the birth canal, or via colostrum and milk. vertical transmission transmission of virus from parent to progeny through the genome, sperm, or ovum or extracellularly (e.g., through colostrum or across the placenta). zoonosis disease which is naturally transmitted to humans from an ongoing reservoir life cycle in animals or arthropods, without the permanent establishment of a new life cycle in humans. viral disease epidemiology is the study of the determinants, dynamics, and distribution of viral diseases in populations. the risk of infection or disease in a population is determined by characteristics of the virus, the host, and the host population, as well as behavioral, environmental, and ecological factors that affect virus transmission from one host to another. epidemiology attempts to meld these factors into a unified whole. the depiction of the interaction of factors favoring the emergence of a viral disease (figure ) , called 'the convergence model', is taken from the us institute of medicine study, microbial threats to health, emergence, detection and response (national academy press, ) . at the center is a box representing the convergence of factors leading to 'the black box', reflecting the reality that many unknown interactions are important virologically and epidemiologically. the foundations of epidemiology predate the microbiological and virological sciences, starting with hippocrates, the greek physician and father of medicine, who in the fourth century bc made important epidemiologic observations on infectious diseases. john snow is called the father of modern epidemiology because he developed excellent quantitative methods while studying the source of a cholera outbreak at the broad street pump in london in . snow was followed by william farr, who in the s advanced the use of vital statistics and clarified many of the principles of risk assessment and retrospective and prospective studies. their vision is reflected in the fast-changing science of epidemiology which is now supported by advanced computer technology, sophisticated statistical methods, and very sensitive and specific diagnostic systems. by introducing quantitative measurements of disease trends, epidemiology has come to have a major role in improving our understanding of the overall nature of disease and in alerting and directing disease control activities. epidemiology is also effective in ( ) clarifying the role of particular viruses and viral variants as the cause of disease, ( ) clarifying the interaction of viruses with environmental determinants of disease, ( ) determining factors affecting host susceptibility, ( ) unraveling modes of transmission, and ( ) field testing of vaccines and antiviral drugs. the comparison of disease experience between populations is expressed in the form of 'rates'. the terms 'incidence rate' and 'prevalence rate' are used to describe quantitatively the frequency of occurrence of infection or disease in populations. 'incidence rate' (also called attack rate) is defined as the ratio of new cases occurring in a population to the size of the population during a specified period of time. prevalence rate is the ratio of the total number of cases occurring in a population to the size of the population during a specified period of time. 'seroprevalence rate' relates to the occurrence of antibody to a particular virus in a population. because viral antibodies, especially neutralizing antibodies, often last a lifetime, seroprevalence rates usually represent cumulative experience with the virus. the term 'case-fatality rate' is used to indicate the percentage of subjects with a particular disease that die from the disease. all these rates may be affected by various attributes that distinguish one individual from another: age, sex, genetic constitution, immune status, pregnancy, nutritional status, and various behavioral and medical care and patient management parameters. the most widely applicable attribute is age, which may encompass immune status as well as various physiological variables. a viral disease is characterized as 'endemic' when there are multiple or continuous chains of transmission resulting in continuous occurrence of disease in a population over a period of time. 'epidemics' are peaks in disease incidence that exceed the endemic baseline or expected rate of disease. the size of the peak required to constitute an epidemic is arbitrary and is related to the background endemic rate and the anxiety that the disease arouses (e.g., a few cases of rabies is regarded as an epidemic, whereas a few cases of influenza is not). a 'pandemic' is a worldwide epidemic. a proper description of an outbreak of disease or an epidemic must include the parameters of 'person (or subjects in the case of animals), place, and time'. such descriptive information is a necessary first step in describing the occurrence, distribution, course, threat, and anticipated action response to the initial recognition of a cluster of cases of disease. much of the initial investigation called for rests in common sense, observational acuity, and an insightful 'index of suspicion'. much of the initial investigation has been termed 'shoe-leather epidemiology'. the trigger for such initial investigation is most often an astute clinician (physician or veterinarian) or an astute pathologist. there are two basic analytic techniques used to investigate relationships between cause and effect and to evaluate risk factors of disease. these are the 'case-control study' and the 'cohort study'. in the case-control study, investigation starts after the disease has occurred -it is a retrospective study, going back in time to determine causative events. although this kind of study does not require the creation of new data or records, it does require careful selection of the control group, matched to the test group so as to avoid bias. the retrospective case-control study lends itself to quick analysis and is relatively inexpensive to carry out. in the cohort study, the prospective study, investigation entails the gathering of new data to identify cause-effect relationships. this kind of study is expensive and does not lend itself to quick analysis as groups must be followed until disease is observed. however, when cohort studies are successful, proof of cause-effect relationship is often incontrovertible. the term 'molecular epidemiology' is used to denote the use of any of a large number of molecular biological methods in support of epidemiologic investigations. for example, with herpesviruses, restriction endonuclease mapping has provided a means of identification of unique viral genotypes -in an epidemiologic study recognized as the first based upon viral molecular characterization, the source of herpes simplex virus causing disease in a hospital newborn nursery was traced to one persistently infected nurse rather than any of several other possible shedders. with rotaviruses and bluetongue viruses, polyacrylamide gel electrophoresis of the segmented viral rna has been used epidemiologically, for example, to unravel outbreaks involving multiple viral variants. panels of monoclonal antibodies have been used to distinguish virus variants for epidemiologic purposes; they have been particularly useful in elucidating host-range and geographic variants of rabies virus. today, partial sequencing has become the most commonly used molecular epidemiologic methodology; partial sequencing of poliovirus isolates recovered from patients indicates whether they are wild type (even local or introduced wild type), attenuated vaccine type, or a vaccine type that has reacquired neurovirulence during human passage. partial sequencing of foot-and-mouth disease viruses can offer the same kind of geographic information of virus movement as has proved so useful in polio control and eradication programs, but because of political sensitivities in some countries a robust international reference laboratory system has not been established that could provide the same kind of practical disease control information as has been the case with polio. thus, with many human and animal viruses molecular epidemiologic studies are flourishing, but more such studies should lead to international reference laboratory systems to guide prevention and control actions. such studies are developing rapidly today to deal with the threat of a human pandemic of avian influenza, but there are many more viral diseases, especially animal diseases, in need of this kind of development. one of the landmarks in the history of infectious diseases was the development of the henle-koch postulates which established the evidence required to prove a causal relationship between a particular infectious agent and a particular disease. these simple postulates were originally drawn up for bacteria, but were revised in by rivers and again in by evans in attempts to accommodate the special problem of proving disease causation by viruses ( table ) . in many cases, virologists have had to rely on indirect evidence, 'guilt by association', with associations based on epidemiologic data and patterns of serologic positivity in populations. today, many aspects of epidemiologic investigation play roles, especially in trying to distinguish an etiological, rather than coincidental or opportunistic relationship between a virus and a given disease. for example, early in the investigation of human acquired immunodeficiency syndrome (aids), before its etiology was established, many kinds of viruses were being isolated from patients and many candidate etiologic agents were being advanced. prediction that the etiologic agent would turn out to be a member of the family retroviridae was based upon years of veterinary research on animal retroviruses and animal retroviral diseases. this prediction was based upon recognition of common biologic and pathogenetic characteristics of aids and animal retroviral diseases. this prediction guided many of the early experiments to find the etiologic agent of aids; later, after human immunodeficiency virus (hiv ) was discovered, its morphological similarity to equine infectious anemia virus, a prototypic member of the genus lentivirus, family retroviridae, was the key to unraveling confusion over the fact that the human virus killed host lymphocytes rather than transforming them as typical oncogenic retroviruses would do. ever since, this essence of comparative medicine has been guiding hiv/ aids research in many areas, including drug design, diagnostics, and vaccine development. hiv/aids epidemiologic research has often been intertwined with research on the several simian immunodeficiency viruses (sivs). seroepidemiology is useful in public health and animal health investigations and in research to determine the prevalence or incidence of particular infections, to evaluate control and immunization programs, and to assess past history when a 'new' virus is discovered. when paired serum specimens are obtained from individuals several weeks apart, the initial appearance of antibody in the second specimen or a rise in antibody titer indicates recent infection. similarly, the presence of specific immunoglobulin m (igm) antibody in single serum samples, indicating recent infection, may be used in seroepidemiologic studies. correlation of serologic tests with clinical observations makes it possible to determine the ratio of clinical to subclinical infections. because of advanced diagnostic/serologic methods, sentinel studies can yield many valuable data in timely fashion about impending disease risks. for example, sentinel chicken flocks are set out for the early detection of the presence of arboviruses such as west nile virus in the united states. these flocks are bled and tested weekly for the presence of virus or antiviral antibody; they provide an early warning of the levels of virus amplification that occur before epidemics. the immunogenicity, potency, safety, and efficacy of vaccines are first studied in laboratory animals, followed by small-scale closed trials, and finally in large-scale open trials. such studies employ epidemiologic methods, rather like those of the cohort (prospective) study. in most cases, there is no alternative way to evaluate new vaccines, and the design of trials has now been developed so that they yield maximum information with minimum risk and acceptable cost. viruses survive in nature only if they are able to be transmitted from one host to another, whether of the same or another species. transmission cycles require virus entry into the body, replication, and shedding with subsequent spread to another host. portals of virus entry into the body include the skin, respiratory tract, intestinal tract, oropharynx, urogenital tract, and conjunctiva. in some cases, viruses use a particular portal of entry because of particular environmental or host-behavior factors and in other cases because of specific viral ligands and host-cell receptors. in many cases, disruption of normal host-defense mechanisms leads to entry that might otherwise be thwarted; for example, papillomaviruses may enter the deep layers of the skin via abrasions, acid-labile coronaviruses may enter the intestine protected by the buffering capacity of milk, and influenza viruses may enter the lower respiratory tract because a drug has dampened cilial action of the respiratory epithelium. the exit of virus from an infected host is just as important as entry in maintaining its transmission cycle. all portals used by viruses to gain entry are used for exit. the table criteria for disease causation: a unified concept appropriate for viruses as causative agents of disease, based on the henle-koch postulates, and modified by a. s. evans important elements in virus shedding are virus yield (from the standpoint of the virus, the more shedding the better) and timeliness of yield (again, the earlier the shedding the better). viruses that cause persistent infections often employ remarkable means to avoid host inflammatory and immune responses so as to continue shedding. for example, the epidemiologically important shedding of herpes simplex viruses and that perpetuates the viruses in populations requires recrudescence of persistent ganglionic infection, centrifugal viral genomic transit to peripheral nerve endings, and productive infection of mucosal epithelium, all in the face of established host immunity. virus transmission may be 'horizontal' or 'vertical'. the vast majority of transmission is horizontal, that is, between individuals within the population at risk. modes of horizontal transmission of viruses can be characterized as direct contact, indirect contact, common vehicle, airborne, vector-borne, iatrogenic, and nosocomial. vertical or transplacental transmission occurs between the mother and her fetus or newborn. some viruses are transmitted in nature via several modes, others exclusively via one mode (see table ). 'direct contact transmission' involves actual physical contact between an infected subject and a susceptible subject (e.g., kissing, epstein-barr virus, the cause of mononucleosis, biting (e.g., rabies); coitus (sexually transmitted viral diseases)). indirect contact transmission occurs via 'fomites', such as shared eating utensils, improperly sterilized surgical equipment, or improperly sterilized non-disposable syringes and needles. 'common vehicle transmission' pertains to fecal contamination of food and water supplies (e.g., norovirus diarrhea). common vehicle transmission commonly results in epidemic disease. 'airborne transmission' typically results in respiratory infections (and less typically in intestinal infections), but these infections may also be transmitted by direct and indirect contact. airborne transmission occurs via large droplets and via very small droplet nuclei (aerosols) emitted from infected persons during coughing or sneezing (e.g., influenza) or from environmental sources. large droplets (> mm in diameter) settle quickly, but droplet nuclei evaporate forming dry particles (< mm in diameter) which remain suspended in the air for extended periods. droplets may travel only a meter or so while droplet nuclei may travel over much longer distances. 'vector-borne transmission' involves the bites of arthropod vectors (e.g., mosquitoes, ticks, and sandflies). 'iatrogenic transmission' involves health care procedures, materials, and workers (e.g., physicians, nurses, dentists, and veterinarians). 'nosocomial transmission' pertains to infections acquired while a patient, human or animal, is in hospital. 'vertical or transplacental transmission' occurs from mother to fetus prior to or during parturition. certain retroviruses are vertically transmitted in animals via the integration of viral dna directly into the dna of the germline of the fertilized egg. other viruses are transmitted to the fetus across the placenta; yet others are transmitted when the fetus passes through the birth canal. another vertical transmission route is via colostrum and milk. vertical transmission of a virus may or may not be associated with 'congenital disease' (i.e., disease that is present at birth) which may be lethal (and the cause of abortion or stillbirth) or the cause of congenital abnormalities. the herpesviruses, especially cytomegaloviruses, and rubella virus cause important congenital diseases in humans, and pestiviruses, such as bovine viral diarrhea virus, in animals. enteric infections are most often transmitted by direct contact and by fomites in a 'fecal-oral cycle' that may include fecal contamination of food and water supplies; diarrheic feces may also splash to give rise to aerosols (droplets and droplet nuclei). respiratory infections are most often transmitted by the airborne route or by indirect contact via fomites in a 'respiratory cycle', that is, virus is shed in respiratory secretions and enters its next host through the nares during inhalation. the respiratory cycle is responsible for the most explosive patterns of epidemic disease in humans and all domestic animal species. perpetuation of a virus in nature depends upon the maintenance of serial infections, that is, a chain of transmission; the occurrence of disease is neither required nor necessarily advantageous. infection without recognizable disease is called 'subclinical' or 'clinically inapparent'. overall, subclinical infections are much more common than those that result in disease. their relative frequency accounts for the difficulty of tracing chains of transmission, even with the help of laboratory diagnostics. although clinical cases may be somewhat more productive sources of virus than subclinical infections, because the latter do not restrict the movement of the infected host, they can be most important as sources of viral dissemination. in most acute infections, whether clinically apparent or not, virus is shed in highest titers during the late stages of the incubation period, before the influence of the host-immune response takes effect. persistent infections, whether or not they are associated with episodes of clinical disease, also play an important role in the perpetuation of many viruses in nature. for example, prolonged virus shedding can reintroduce virus into a population of susceptibles all of which have been born since the last clinically apparent episode of infection. this is important in the survival of rubella virus in some isolated populations. sometimes the persistence of infection, the production of disease, and the transmission of virus are dissociated; for example, togavirus and arenavirus infections may have little adverse effect on their reservoir hosts (arthropods, birds, and rodents), but transmission may be very efficient. on the other hand, the persistence of infection in the central nervous system, as with measles virus in subacute sclerosing panencephalitis (sspe), is of no epidemiological significance, since no infectious virus is shed from this site. the virulence of the infecting virus may directly affect the probability of its transmission. the classic example of this is rabbit myxomatosis. in australia, mosquito-borne transmission of myxoma virus was found to be most effective when infected rabbits maintained highly infectious skin lesions for several days before death. highly virulent strains of the virus were found to kill rabbits so quickly that transmission did not occur, and naturally attenuated strains were found to produce minimal lesions that healed quickly and did not permit transmission. virus strains at either extreme of this virulence spectrum were found not to survive in nature, but virus strains of intermediate virulence have circulated for many years. with most viruses, endemic or epidemic transmission leads to a level of immunity in the host population that affects or even interrupts further transmission. the 'herd immunity' effect is countered in some cases by viral antigenic variation. for example, influenza viruses undergo genetic variations ('shift' and 'drift') such that persons immune to previously circulating virus strains are susceptible to new strains. assessing these genetic changes is the main objective of laboratory-based surveillance programs, which in turn are the basis for decisions on the formulation of each year's influenza vaccine. it is self-evident that the long-term survival of a virus requires that it be continuously transmitted from one host to another. in general, for rapidly and efficiently transmitted viruses such as many respiratory viruses, local survival of the virus requires that the susceptible host population be very large. a virus may disappear from a population because it exhausts its potential supply of susceptible hosts as they acquire immunity to reinfection with the same virus. depending on duration of immunity and the pattern of virus shedding, the 'critical population size' varies considerably with different viruses and with different host species. the most precise data on the importance of population size in acute nonpersistent infections come from studies of measles. persistence of measles virus in a population depends upon a continuous supply of susceptible children. analyses of the incidence of measles in large cities and in island communities have shown that a population of about half a million persons is needed to ensure a large enough annual input of new susceptible hosts, by birth or immigration, to maintain measles virus in the population. because infection depends on respiratory transmission, the duration of epidemics of measles is correlated inversely with population density. if a population is dispersed over a large area, the rate of spread is reduced and the epidemic may last longer, so that the number of susceptible persons needed to maintain transmission chains is reduced. on the other hand, in such a situation a break in the transmission chain is much more likely. when a large proportion of the population is initially susceptible, the intensity of the epidemic builds up very quickly and attack rates are almost % ('virginsoil epidemic'). on the other hand, when measles vaccination programs are implemented properly the virus disappears completely from the regional population. because most viruses are host-restricted, most viral infections are maintained in nature within populations of the same or related species. however, there are a number of viruses that may have multiple hosts and spread naturally between several different species of vertebrate host, for example, rabies and eastern equine encephalitis viruses. the term 'zoonosis' is used to describe multiple-host infections that are transmissible from animals to man. the zoonoses, whether involving domestic or wild animals or arthropods, usually represent important problems only under conditions where humans are engaged in activities involving close contact with animals or exposure to arthropods. many viral zoonoses are caused by arboviruses. arboviruses have two classes of hosts, vertebrate and invertebrate. over arboviruses are known, of which about cause disease in humans and in domestic animals; some of these are transmitted by ticks, some by mosquitoes, and yet others by phlebotomine flies (sandflies) or culicoides spp. (midges). arthropod transmission may be 'mechanical', where the arthropod acts as a 'flying pin', or more commonly, 'biological', involving replication of the virus in the arthropod vector. the arthropod vector acquires virus by feeding on the blood of a viremic person or animal. replication of the ingested virus, initially in the arthropod's gut, and its spread to the salivary glands takes several days; the interval varies with different viruses and is influenced by ambient temperature. virions in the salivary secretions of the vector are injected into human or animal hosts during subsequent blood meals. most arboviruses have localized natural habitats in which specific receptive arthropod and vertebrate hosts are involved in the viral life cycle. vertebrate reservoir hosts are usually wild mammals or birds; humans are rarely involved in primary transmission cycles, although the exceptions to this generalization are important (e.g., venezuelan equine encephalitis, yellow fever, and dengue viruses). humans are in most cases infected incidentally, for example, by the geographic extension of a reservoir vertebrate host and/or a vector arthropod. ecological changes produced by human activities disturb natural arbovirus life cycles and have been incriminated in the geographic spread or increased prevalence of arbovirus diseases. from the time of william farr, who studied epidemic disease problems in the s, mathematicians have been interested in 'epidemic curves' and secular trends in the incidence of infectious diseases. with the development of computer-based mathematical modeling techniques, there has been a resurgence of interest in the population dynamics of infectious diseases. there has also been a resurgence in controversies surrounding the use of models; critics say 'for every model there is an equal and opposite model'. so, the proof of the value of models lies in their practical application, and in recent years there have been more and more successes. for example, when for counterterrorism reasons universal smallpox vaccination was being considered, models that showed that vaccine could be used effectively after rapid detection of a terrorism incident led to a decision to stockpile, but not widely use vaccine. as another example, when a foot-and-mouth disease epidemic raged in the united kingdom in , a model showed that only the most vigorous stamping-out campaign could get ahead of the movement of the virus across the country. the model, seeming eminently logical now, importantly provided the kind of veracity and political will needed to accelerate the stamping-out campaign. models may be used to determine ( ) patterns of disease transmission, ( ) critical population sizes to support the continuous transmission of viruses with short and long incubation periods, ( ) the dynamics of endemicity of viruses that become persistent in their hosts, and ( ) the variables in age-dependent viral pathogenicity. computer modeling also provides useful insights into the effectiveness of disease control programs. much attention has been given to modeling the future of the aids epidemic in the united states and the rest of the world. such models usually start with historical data on the introduction of the etiologic virus, hiv , proceed to the present stage of the epidemic where the disease has become well established in many countries and in fewer countries subject to prevention and treatment strategies, and then proceed to project its course into the future. during the first years of the aids epidemic in the united states, african countries, and then in asian countries, most models underestimated developing trends; more recently models have become more accurately predictive -but in many places more and more sobering. knowledge of the epidemiology and modes of transmission of infectious diseases is critical to the development and implementation of prevention and control strategies. data on incidence, prevalence, and mortality contribute directly to the establishment of priorities for prevention and control programs while knowledge of viral characteristics and modes of transmission are used in deciding prevention strategies focusing on vaccine development and delivery, environmental improvements, enhancement of nutritional status, improvement in personal hygiene, and behavioral changes. see also: disease surveillance; viral pathogenesis; zoonoses. prevalence of the disease is significantly higher in subjects exposed to the putative virus than in those not so exposed. . incidence of the disease is significantly higher in subjects exposed to the putative virus than in those not so exposed temporally, the onset of disease follows exposure to the putative virus, always following an incubation period a regular pattern of clinical signs follows exposure to the putative virus, presenting a graded response, often from mild to severe a measurable host-immune response, such as an antibody response and/or a cell-mediated response, follows exposure to the putative virus experimental reproduction of the disease follows deliberate exposure of animals to the putative virus, but nonexposed control animals remain disease free. deliberate exposure may be in the laboratory or in the field, as with sentinel animals elimination of the putative virus and/or its vector decreases the incidence of the disease prevention or modification of infection, via immunization or drugs, decreases the incidence of the disease control of communicable diseases manual, th edn mandell, douglas, and bennett's principles and practice of infectious diseases the epidemiology of viral infections veterinary virology fields virology evolution of viral diseases virus dynamics: mathematical principles of immunology and virology emerging microbial threats to health in the st century. institute of medicine/ national academy of sciences microbial threads to health, emergence, detection and response veterinary epidemiology general features all rights reserved. the lymphocryptoviruses (lcvs) present in old world nonhuman primates, including ebv-like viruses of chimpanzees and rhesus monkeys. these viruses share homologous sequences and genetic organization, and infect the b lymphocytes of their host species, resulting in the establishment of latent infection in vivo and transformation key: cord- -vubszdp authors: li, lucy m; grassly, nicholas c; fraser, christophe title: genomic analysis of emerging pathogens: methods, application and future trends date: - - journal: genome biol doi: . /s - - - sha: doc_id: cord_uid: vubszdp the number of emerging infectious diseases is increasing. characterizing novel or re-emerging infections is aided by the availability of pathogen genomes. in this review, we evaluate methods that exploit pathogen sequences and the contribution of genomic analysis to understand the epidemiology of recently emerged infectious diseases. when a pathogen crosses over from animals to humans, or an existing human disease suddenly increases in incidence, the infectious disease is said to be 'emerging'. the number of emerging infectious diseases (eids) has increased over the last few decades, driven by both anthropogenic and environmental factors [ ] . these include the expansion of agricultural land, which increases the exposure of livestock and humans to infections in wildlife [ ] ; a greater volume of air traffic, enabling eids to rapidly spread across the world [ , ] ; and climate change, which alters the ecology and density of animal vectors, thereby introducing diseases to new geographic locations [ ] . novel strains of existing pathogens also have the potential to cause large epidemics. the over-and misuse of antimicrobial drugs have contributed to the growing number of drug-resistant pathogen strains [ , ] . detecting, characterizing and responding to an eid requires co-ordination and collaboration between multiple sectors and disciplines. laboratory-based research helps to characterize the pathogen and its interactions with host cells, but is less useful for quantitative understanding of population-level disease dynamics. modeling approaches enable a large number of hypotheses to be tested, which might not be logistically or ethically feasible in laboratory and field experiments. in addition to characterizing past disease dynamics, modeling future trends informs decisions regarding outbreak response and resource allocation [ ] . modeling plays an especially important role in epidemiological studies of infectious disease spread, because the transmission of infectious disease between individuals is not directly observable. at the individual level, transmission times and who infected whom are typically unknown. and at the population level, disease burden needs to be inferred from observable data. important public health questions such as how quickly an epidemic spreads and how many people will be infected are hard to quantify without a mechanistic understanding of underlying factors driving disease transmission. by expressing disease spread in mathematical terms, statistical properties of epidemics can be estimated to help address specific questions regarding disease spread and control efforts [ ] . another discipline contributing to the study of eids is pathogen genomics. as sequencing technology has become more accessible and affordable, genetic analysis has played an increasingly important role in infectious disease research. sequencing pathogens can confirm suspected cases of an infectious disease, discriminate between different strains, and classify novel pathogens. in addition to examining individual pathogen sequences, multiple sequences can be analyzed together using phylogenetic methods to elucidate evolutionary [ ] and transmission [ ] history. just as mathematical models of disease transmission help to capture the epidemiological properties of an infectious disease, modeling the molecular evolution of pathogen genomes is important for phylogenetic methods. besides characterizing the genetics and evolution of a pathogen, mathematical models used in population genetics link demographic and evolutionary processes to temporal changes in population-level genetic diversity. the coalescent population genetics framework was developed so that demographic history could be inferred from the shape of the genealogy linking sampled individuals [ , ] . more recently, the birth-death model has been applied to infectious diseases to infer epidemiological history from a genealogy [ , ] . given the link between pathogen evolution and disease transmission, there is a trend towards integrating both epidemiologic and genetic data in the same analytical framework [ ] [ ] [ ] . in this review, we provide an overview of recent developments in genomic methods in the context of infectious diseases, evaluate integrative methods that incorporate genetic data in epidemiological analysis, and discuss the application of these methods to eids. over the last two decades, sequence data have increased in quality, length and volume due to improvements in the underlying technology and decreasing costs. as a result, pathogen sequences are regularly collected during routine surveillance and clinical studies. just as mathematical modeling can be used to analyze surveillance data to reveal details of disease transmission (box ), analysis of pathogen genomes employs mathematical frameworks to elucidate pathogen biology, evolution and ecology (figure ). at the most basic level, mathematical models are used to find the optimal alignment of pathogen sequences. multiple sequence alignment is useful for finding highly conserved or variable regions, shedding light on the molecular biology of the pathogen. furthermore, coupling sequences with clinical information can help identify the contribution of polymorphic sites to disease. revealing the evolutionary history of a pathogen requires a quantitative description of relatedness. based on polymorphic sites in the sequence alignment, a model of sequence evolution is then used to reconstruct the phylogeny [ ] . often, there is insufficient genetic diversity in the sample to fully infer the phylogeny without ambiguity. in such a case, it is useful to consider a tree as an unknown set of parameters and obtain its posterior probability distribution using a bayesian framework, such as the markov chain monte carlo (mcmc) approaches [ , ] . biological samples from which pathogen genetic material is sequenced are usually associated with geographic or temporal information (figure b ). when this additional information is available, phylogenetic methods can reveal the spatiotemporal spread of the pathogen in the population. if an outbreak is densely sampled, then the pathogen phylogeny provides information about the underlying transmission network and helps to uncover who infected whom [ , ] , though phylogenetic clustering alone is usually not sufficient to prove direct transmission or direction of infection ( figure b) . incorporating sampling times helps to convert a phylogeny specified in units of nucleotide substitutions to a phylogeny specified in units of time [ ] . the conversion is straightforward if sequence evolution follows a strict molecular clock, whereby the rate of substitution remains constant over time. however, selection pressure and population bottlenecks can lead to changes in the rate of substitution [ ] . more flexible models have been developed to incorporate time-varying rates of evolution [ , ] . with branch lengths in units of real time, the start date of an epidemic can be estimated. whereas phylogenetics aims to delineate the relationship between individuals, population genetics aims to link population processes to observed patterns of genetic diversity. inferences regarding pathogen population history are based on the genealogy, or ancestry, of sequences from sampled individuals, and often carried out in a retrospective population genetics framework known as the coalescent [ ] (box ). a genealogy describes the ancestry of sampled individuals. going backwards in time, pairs of lineages coalesce when they share a common ancestor, until the last two lineages coalesce at the time of the most recent common ancestor (tmrca) for the entire sample. since the turn of the century, the coalescent has been increasingly applied to infectious disease research to infer epidemic history from pathogen sequences, thereby linking pathogen evolutionary history to disease epidemiology ( figure c ). the method is especially useful for analyzing infectious diseases with mild or asymptomatic infections, for which case-based surveillance data severely underestimate prevalence, because the coalescent assumes a small sample compared to the population size [ ] [ ] [ ] . other approaches have been developed to make epidemiological inferences from genetic data. of particular note is the birth-death model [ ] , which describes the rates of transmissions, recoveries and deaths, and sampling events in terms of the sample genealogy [ ] . just as there are coalescent methods incorporating population structure [ ] [ ] [ ] and compartmental models [ ] [ ] [ ] , similar methods exist in the birth-death framework [ , ] . unlike the coalescent framework, the birthdeath model is still valid for densely sampled populations, which makes it more useful for studying small outbreaks. however, accurately inferring epidemiological parameters depends on correctly specified sampling proportions [ ] . although the two approaches are methodologically different, both aim to reconstruct pathogen population history and produce estimates of epidemiological parameters, such as the reproductive number (r ). the focus on the coalescent framework in this review is due to its more pervasive use in the literature and its greater versatility when integrated with epidemiological models compared to birth-death models. because of the simplistic assumptions of population genetics models, the population size inferred using coalescentbased methods cannot be directly interpreted as pathogen population size (prevalence of infection). it is rather the effective population size, n e (box ), which refers to the size of a wright-fisher population that would produce the same level of genetic diversity as observed in the sample. in real populations, the variance of the offspring distribution (box ) is higher than expected in a wright-fisher population due to heterogeneity in host infectiousness, non-random mixing of the population, and migration events. the consequence of a large variance is that there is a greater discrepancy between the effective and census population sizes [ ] . accounting for the dispersion of the offspring distribution is especially important when analyzing infectious disease data because of the widespread occurrence of transmission heterogeneity [ ] . another statistical property of epidemics affecting the results of modeling studies is the generation time distribution, which describes the time between infection of the primary case and of secondary cases. obtaining an estimate of the generation time is important for two reasons. first, estimates of r from the initial growth rate of an epidemic depend on the generation time distribution [ ] . as r is the mean of the offspring distribution, its value affects the relationship between the effective population size, n e , and the census population size, n. second, the coalescent model was originally specified in units of generations, and so estimates in this framework need to be converted to natural units using the generation time, t g . because transmission events are rarely observed, the generation time distribution is often approximated by the distribution of the serial interval, which is the time between onset of symptoms in the primary and secondary cases. the two distributions generally share the same mean but might have different variances [ ] . furthermore, the observed generation time decreases as the epidemic grows but increases again after the epidemic peak due to right censoring [ ] . as both sequence and surveillance data contain information regarding the transmission process, simultaneously analyzing both datasets should yield more accurate estimates of epidemiological parameters than separate analyses [ ] . the recently established discipline of phylodynamics takes an interdisciplinary approach to understand the pathogen phylogenetics and epidemiology in terms of disease transmission. most efforts thus far have focused on enhancing phylogenetic and population genetic analyses by incorporating spatial and temporal information about the sequences. the molecular clock model assumes a constant rate of evolution and thus helps to estimate the time of the most recent common ancestor of the sample, which approximates the start date of an epidemic. molecular clock analysis has been used to date the emergence of a range of emerging pathogens from hiv [ ] to multidrug-resistant streptococcus pneumoniae [ ] . linking geographic information with sequences can reveal the spatial spread of infectious disease. phylogenetic reconstruction of seasonal influenza (h n ) sequences has revealed the contribution of viral circulation in temperate regions to the global genetic diversity of influenza, and determined that not all epidemics in temperate regions are seeded by strains from south east asia [ , ] . also using global sequences, hepatitis c virus (hcv) subtypes were shown to spread from developed to developing countries [ ] . finally, phylogeographic analysis of methicillin-resistant staphylococcus aureus samples identified england as the source of the emrsa- lineage [ ] . by contrast, there have been relatively few studies incorporating genetic data into epidemiological frameworks. although genetic analysis plays an important role in elucidating transmission links in disease outbreaks [ , , ] , its integration with epidemiological models to understand population-level disease dynamics has been more limited. in one of the first papers to link coalescent inference to mathematical models in epidemiology, the effective population sizes of hiv- subtypes a and b were estimated from the maximum likelihood trees of viral sequences [ ] . in addition to revealing population sizes, pybus et al. [ ] estimated the r values of hcv subtypes ( a, b, and ) by inferring the epidemic growth rate from viral genealogy. taking integration a step further, the coalescent process has been described for compartmental epidemiological models such as the susceptible-infected-recovered (sir) model, thereby enabling epidemiological parameters to be inferred from the genealogy [ ] . to infer demographic history from both pathogen genomes and epidemiological data, rasmussen et al. [ ] developed a markovian framework in which the population size at each time step was estimated by taking into account both the surveillance data and the genealogy. the epidemic history reconstructed using both datasets was more accurate than when analyzing each type of data separately. in all the above methods, the genealogy of the sampled sequences was fixed. however, there might be great uncertainty regarding the order and the timing of coalescence, especially if the sequences are sampled within a short time period. while genealogical reconstruction using bayesian mcmc approaches allows phylogenetic uncertainty to be incorporated into estimates of population size [ , ] , an integrative model is lacking in which uncertainties arising from both genetic and epidemiological data are incorporated during demographic reconstruction. models of pathogen evolution and mechanistic models of disease spread have increased in complexity. there is also greater computational power to test these models with data. however, these sophisticated models have mostly been applied to infectious diseases for which abundant data are available. for example, new methods are most often tested on the hiv- pandemic [ , , , ] , for which data have been extensively collected from various settings and sources since the virus was first characterized three decades ago. it is worthwhile to evaluate how genomic methods have been applied to other diseases that have emerged more recently. in this section, we will present three case studies of recently emerged infectious diseases to illustrate the power and shortcomings of genomic methods discussed in this review. since emerging in guinea in march , ebola virus (ebov) has spread to other countries in western africa, resulting in the largest outbreak of ebola since it was first identified in . the first viral genomes were made available just a month after alarm was raised about a new ebola outbreak in guinea [ ] , with further sequences collected in sierra leone [ ] . by aligning all the genomes, a number of polymorphic sites were identified, including eight in highly conserved regions of the genome. further association studies are needed to clarify the role of these genetic variants in determining disease outcome. using the sampling dates of the sequences and a molecular clock model, phylogenetic analysis of ebov sequences revealed a start date of february in guinea, spreading to sierra leone by april [ ] . uncovering the relationship between the ebov lineage and previous ebov outbreaks has proved trickier than understanding the disease dynamics during the outbreak. initial phylogenetic analysis suggested that lineages causing the present outbreak did not cluster with ebov strains that caused earlier outbreaks in central africa [ ] . however, dudas and rambaut [ ] noted that the divergence of guinea sequences from those of previous outbreaks was because they were sequenced most recently and had accumulated the highest number of substitutions. assuming that the ebov genome followed a molecular clock model, the authors re-rooted the tree to a lineage that caused an outbreak in [ ] . instead of silently circulating in west africa, the ebov lineage causing the current outbreak likely descended from a lineage that previously caused outbreaks in the democratic republic of congo. these studies highlight two issues. first, correct rooting of a phylogeny is important for accurate inference of past epidemic history. correct rooting can be achieved by using an out-group, but one was not available in the case of this ebov strain. this leads onto the second issue. without sequences from animal hosts, the mechanism by which ebov was sustained between outbreaks remains unknown. middle east respiratory syndrome coronavirus (mers-cov) first appeared in saudi arabia in , and has since been reported in several neighboring countries in the arabian peninsula and on other continents [ ] . despite the dearth of sequence data, coalescent-based analysis of genomic sequences produced estimates of the tmrca (march ; % confidence interval (ci): november to june ), r ( . ; % ci: . , . ), and doubling time ( days; % ci: , days) [ ] . without further sequencing of the animal reservoirs, the authors could not infer whether these estimates applied to the animal reservoir or the human epidemic, because the methods are agnostic as to where transmission and evolution occur. the credible intervals around the estimates were unsurprisingly large given the small sample size. unlike the ebov outbreak, which is sustained by human-to-human transmission [ ] , there appears to have been multiple introductions of mers-cov into the human population. identification of the animal reservoir is therefore crucial for establishing risk factors of infection and planning appropriate interventions to control the disease. since bats are reservoirs for other coronaviruses, their being a reservoir host is possible. a nucleotide-long region of the rna-dependent rna polymerase gene was found to be % identical between a viral sample from a patient in saudi arabia and from a bat nearby, though the region is known to be highly conserved [ ] . however, antibodies against human mers-cov have been detected in dromedary camels [ ] , the camel mers-cov genome is similar to human mers-cov [ ] , and there are reports of close contact between patients and camels [ ] . phylogenetic analysis of coronavirus sequences from bats, dromedaries and humans indicate a bat origin, with dromedary camel as an intermediate host [ ] . it is possible that there are other animal reservoirs not yet sampled, which highlights the need to carry out extensive animal surveillance to characterize the emergence of an infection in humans. unraveling the complex evolutionary history of pandemic h n influenza with sequences collected over three decades from humans, pigs and birds, the origin of the pandemic h n influenza a strain (pdmh n or 'swine flu') was elucidated soon after emergence. within two months of the first reported case of swine flu in humans, genomic analysis of the novel influenza strain had been carried out. a phylogeny was constructed for each of the eight genomic segments with sequences from humans, swine and birds. comparison of these eight phylogenies revealed a complex history of reassortment with a mixture of gene segments from all three groups. the start of the pandemic was estimated to be the end of or early , and the dates of the reassortment events leading to pdmh n were also obtained [ ] . without good surveillance of influenza in the animal reservoir, the origin of the novel strain would have been difficult to uncover. by analyzing hemagglutinin sequences collected over a one-month period, the start date of the epidemic was estimated to be in late january [ ] . repeating the phylogenetic and molecular clock analyses with a further sequences shifted the estimated start date two weeks earlier. fitting an exponential growth model to the sequence data, r was estimated to be . , slightly lower than inferred from epidemiological data but with overlapping confidence intervals. to determine at which point during the pandemic coalescent analysis would have provided accurate and precise estimates of evolutionary rate, r and tmrca, real-time estimates of these parameters were obtained for genomic sequences collected in north america [ ] . accurate estimates could have been obtained as early as may, when viral genomes had been sequenced. more precise estimates could have been obtained by the end of june, when had been sequenced. however, inclusion of more sequences of longer length only slightly improved the accuracy of initial estimates [ ] . most statistical models in population genetics have focused on the application of such methods to viruses, although this bias is perhaps unsurprising given the large proportion of eids caused by viruses [ ] . whole-genome sequencing of bacterial isolates is becoming more widespread, and can help to uncover genetic determinants of clinical severity, elucidate pathogen-host interactions, and quantify evolutionary rates at within-and between-host levels [ ] . epidemiological investigations using bacterial genomes have also been possible. even though bacteria acquire point mutations at a lower rate per base than viruses, longer bacterial genomes have provided sufficient genetic resolution for phylogenetic analysis. for example, whole-genome sequencing has been used to refine the tuberculosis transmission network built using contact information [ ] , and to investigate an outbreak of methicillin-resistant staphylococcus aureus in a hospital and surrounding community in near real-time [ ] . the need for longer sequences when conducting epidemiological studies of bacterial infections adds to the per-sample cost of sequencing, and more computational resources are required for coalescent-based inference of pathogen history. however, this latter limitation may be overcome by only analyzing polymorphic sites if samples are similar. demographic reconstruction of emerging bacterial pathogens using coalescent-based approaches has been limited compared to work on viral pathogens. in one such study, the temporal changes in genetic diversity of streptococcus pneumoniae in iceland were estimated based on the coalescent model [ ] . this study was limited to a single multidrug-resistant lineage in a single location, with data collected over decades. over longer evolutionary time-scales, the accumulation of diversity through recombination can obscure phylogenetic relationships. more complex evolutionary models would be required to taken into account these genomic changes, increasing the uncertainty surrounding demographic estimates from genomic data. in addition to performing analyses with longer sequences, there is also a need to develop methods that exploit as many sequences in the sample as possible. for population studies, available sequences are often subsampled to remove individuals from the same household or in the same close contact network to have a representative sample of the population. furthermore, sequences from the same individuals are often discarded, though these may be informative for within-host evolution. although some effort has been made to link within-host to between-host evolution [ , ] , the effect of within-host evolution on population genetic inference is still not well studied. combining analyses across different scales could improve the accuracy of epidemiological predictions and provide better mechanistic explanations of observed trends. genomic studies have contributed to better understanding of eids and their spatiotemporal spread. sophisticated statistical methods have been developed to uncover the epidemiological features of infectious diseases based on the genealogy of their sequences. there is also growing when the distribution cannot be computed analytically [ ] . obtaining estimates of r and t g is not always sufficient to predict epidemic trajectory if there is significant heterogeneity between individuals. the offspring distribution with mean r and variance σ describes the probability distribution of the number of secondary infections caused by each infected individual. in compartmental models, the offspring distribution is not explicitly specified but follows from the specification of the model -in the case of the sir model it follows a geometric distribution. for certain diseases, the offspring distribution is more dispersed than captured by the geometric distribution [ ] . in other words, most individuals cause no further infections whereas a few individuals are super-spreaders who cause the majority of infections. accurate estimate of σ is important for predicting epidemic outcome and assessing control measures. effort to integrate genomic analysis with analysis of epidemiological data. in recent cases of eids, genomic data have helped to classify and characterize the pathogen, uncover the population history of the disease, and produce estimates of epidemiological parameters. just as compartmental models can be fitted to surveillance data to infer the epidemiological dynamics of an infectious disease (box ), the coalescent framework allows inference of population history from pathogen sequences. the coalescent model describes the statistical properties of the genealogy underlying a small sample of individuals from a large population. in the simplest case, the forward-time dynamics of the population is assumed to follow the wright-fisher model, in which the haploid population has discrete, non-overlapping generations, undergoes neutral evolution, and remains the same size [ , ] . extensions to the coalescent have assumed more complex population dynamics described by deterministic population equations [ ] , compartmental disease models [ ] , or non-parametric approaches [ , , , ] . within this framework, going backwards in time, 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doc_id: cord_uid: i d a simple two-cohort sir like model can explain the qualitative behaviour of the logarithmic derivative estimations of the covid- epidemic evolution as observed in several countries. the model consists of a general population in which the r_ value is slightly below , but in which a super-spreading small subgroup with high r_ , coupled to the general population, is contaminating a significant fraction of the population. the epidemic starts to slow down when herd immunity is reached in this subgroup. the dynamics of this system is quite robust against non-pharmaceutical measures. the covid- epidemic dynamics has to be understood in order to have an intelligent policy that optimizes society's well-being. without understanding that dynamics, one might take measures that are highly ineffective and/or place a huge burden on society, with a cost-benefit ratio that is far from optimal. unfortunately, not much high-quality data is available that allows us to test against sophisticated epidemiological models. the most important data, which describes the propagation of infections, is simply not publicly available for most populations . confirmed cases depend strongly on ever changing policies of testing and are potentially severely biased. they are very bad proxies to estimate infections. hospitalisation entries are also depending on decisions which are different from country to country, and may be changing over time. the only more or less reliable data are the numbers of dead, which are most probably within a factor or from the actual numbers of victims of covid- . the problem with this proxy is that there's a long delay and a large smoothing in time, due to the probability distribution that links the event of being contaminated with dying of the disease. the simple sir model suggests that one can obtain an estimate of the β − γ factor by calculating the deconvolved logarithmic derivative of a proxy curve for contamination. in a recent paper [ ] , the logarithmic derivative of the curves of the number of deceased people of different countries has been calculated, for countries that have applied different sets of non-pharmaceutical policies, and have different climates. the behaviour . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . of this logarithmic derivative seems to be quite universal, independent of the measures taken, and of other specific factors. the universal curve is a more or less linear decrease of the logarithmic derivative, starting around . per day, and steadily decreasing to a value of about - . , and then remains more or less constant. this might be an effect of the policies put in place, but it might also be the natural dynamics of the epidemic, independent of any policy. we re-calculated the same kind of curve here, for a few selected european countries. we took the data from [ ], and we applied a moving -day average to have less noisy data, and remove weekly cyclic phenomena. calculating the logarithmic derivative of the reported deceased cases for some european countries, we confirm the behavioural findings of the cited paper: we note the extreme similarity between all these curves. only italy has a somewhat slower decay, but it starts out also around . . all these curves level off towards the same slightly negative value of about - . . it is also intriguing that the tendency sets in quite a few weeks before one expects to see the effects on the deaths of the lock-down policies put in place in some countries. it was the essential point raised in [ ] . this doesn't necessarily mean that those policies have no effect ; it means that the linear decrease is not much affected by those policies. we will come to that. a more interesting curve to look to is that of brazil. brazil is interesting for several reasons. the first one is that the country is in the southern hemisphere. all seasonal effects should be opposite there. the second one is that the policies put in place are quite different from those in europe (only very partial lock-downs). . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . we notice again the same behaviour. however, it seems that the "constant part" is rather slightly positive rather than negative even though the data is noisy and it is not clear if there's still not a slope downward. we find again a similar behaviour by analysing for instance, the entries in belgian hospitals since march . these data were taken from [ ]. unfortunately, there is no data available before this date, so the plot is truncated on the left. we had to average the entries over a week because there were weekly periodic effects and the daily data was too noisy, but if one averages over days, and one calculates the logarithmic derivative of the hospital entries, one finds again the same universal curve: in this paper, we try to build a model that displays a similar qualitative behaviour. we do not fit that model to any real-world data, and we do not pretend at all to . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint have a working and predictive model for the covid- epidemic. we are only exploring a potential mechanism that might explain the universal qualitative behaviour of the logarithmic derivative of observed data by building a very simple model exhibiting a similar qualitative behaviour. in the classical sir model, there are compartments: the susceptible population, the infected and contagious population, and the recovering and non-susceptible/noncontagious population. in reality we only care about the first two compartments, because we want to study the dynamics of contagion, not of recovery. the sir model models the contagion dynamics with two hypotheses. the first is that any member of the i compartment will potentially contaminate β people per day, but of these β potential people, only a fraction s/n is actually susceptible to be infected. the second is that each member of i has a probability of γ per day to become a member of r (that is to say, to lose its contagious statute, and to be removed from the people concerned in the contagion process). essentially, it comes down to saying that on average, a contagious person is contagious for about /γ days. the equations implementing the above hypotheses are as follows: the logarithmic derivative of the infected cases, or of any proxy that is proportional to the infected cases (such as the number of dead) equals: we recall that r is defined to be: and is interpreted as being the average number of people that a contagious person will contaminate over time, if the population is naive (that is, s = n ). if r > , the illness can start propagating in a naive population. in the same vain, r(t) is defined as: and is interpreted as being the instantaneous number of people a contagious person will contaminate over time in a population that has already some immunity. if r > , . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . the illness continues to propagate, if r < , the epidemic starts dying out. the condition r = equals the condition di dt = and is the point where the number of contaminated people starts diminishing (when the epidemic starts dying out). it is not the point where no more new infections are happening, but it is the point where herd immunity has been reached. if at that point, there are still a lot of contagious people, they will continue for a while to contaminate others, but their numbers will decrease. herd immunity is reached when: in other words, when a fraction − r of the population got ill. in an sir model, initially the logarithmic derivative equals β − γ, and, as the fraction of the susceptible population s/n decreases (as "immunity" increases), the value evolves towards an asymptotic value between and −γ. when the epidemic ends, the logarithmic derivative tends towards a constant. at first sight, this corresponds exactly to what has been observed for the covid- epidemic proxies: a steady almost linear decrease from a value around . towards a value close to - . or so, followed by a constant value. however, that would mean that "herd immunity" has been reached in those populations. most preliminary studies seem to indicate that in most countries, herd immunity is still far away, and only about % or so of the population has been removed from the "susceptible" status. in order to try to reconcile the behaviour of the logarithmic derivative which points to "herd immunity reached" and the low attack rate in the overall population, we propose to consider a small super-spreader subgroup in the population. we consider a small group which is initially also in a susceptible state, and which will also evolve into its own infectious state, and end up in a recovering state. however, we suppose that this small group can infect also a significant amount of people in the general population. the index is used for the general population (of sizen ) and the index is used for our super spreader group (of size n s ). if we were to have two separate groups which do not interact, but of which the second group has a much more contaminating behaviour than the first group, we would obtain the following set of model equations: . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint the recovery time for both contaminating groups, which is described by γ, is of course the same, but the first group has a coefficient of daily potential contaminations equal to β and the second group has a much higher β number of potential daily contaminations. it isn't very interesting to study this model, because they are simply two independent sir models. it becomes more interesting if we introduce the fact that our super spreaders do contaminate also a lot of people from the first group: the difference with the previous set of equations resides in the extra term β c i , added to β i in the first two equations. it means that each super spreader (in the box i ) will on average contaminate, on top of his colleagues from group , potentially also β c people from group per day. so people from group can be contaminated by other people from group , or from super spreaders from group . we propose the following values of the parameters for our first model, model , which will serve as baseline: the size of the population is like the population of belgium, with a super spreader cohort of about people. in the general population, r = β γ = . which means that the virus doesn't propagate epidemically in the general population. however, in the spreader cohort, r = . . and a spreader contaminates people per day in the general population. the average time that one is contagious equals t c = gamma = . days. we start out with people contaminated in the general population, but people in the spreader cohort on day . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . the spreader cohort simply follows the laws of a simple sir model, and reaches rather quickly herd immunity and beyond (more than % of the spreader cohort ends up infected). the spreader cohort serves also as a driver for the dynamics in the general population, and the general population logarithmic derivative follows the spreader cohort logarithmic derivative. the slowdown of the epidemic is slower in the general population than it was in the super spreader cohort because β s /n s ends up being smaller than β s /n . as such, it seems that the epidemic is still "keeping on" for a long time in the population. at the same time, the speed of infection slows down significantly after weeks while only % of the population is infected, which seems low as compared to the estimated necessary herd immunity if one interprets this dynamics in the frame of a simple sir model. in the end, about % of the population will end up having been infected. if we increase now β to . , keeping all the rest equal, so we bring the general population "closer to criticality", and we call this model , we obtain: cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint the dynamics is very similar to the base model, except that we now have about % of the general population that will get infected. we see that bringing the population close to criticality (r close to ) can significantly increase the amount of people that get infected. however, lowering β instead of increasing it, down to . from the . of the base model, will reduce the amount of infected people only moderately (we will obtain about % of the people infected). in order to reduce β from down to . takes a significant effort for a non-proportional gain in infected people. reducing the coupling β c from . down to . will have a larger effect on the people involved: only . % gets infected. trying to reduce the self-infection rate in the super spreaders (bringing β down from . to . ) will not reduce the end result much in the general population, but will spread out the epidemic quite longer in time. we call this last modification: model . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint as we can see, the general population will end up still with % infected cases, but everything is much more spread out in time. let us look at a case where the illness is epidemic in the general population, be it at a very low level. that is to say, let us consider an r slightly above . we put β at . (so slightly larger than γ which is . ), which gives us an r value of . . herd immunity corresponds to % of the population. we also diminish the coupling of our super spreaders to the general population to a much lower value by putting β c to . . we call this model . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. as we can see, the behaviour is still very similar to the behaviour of the base model. however, this time, the logarithmic derivative remains a very long time slightly above . it is remarkable that even with a very slight coupling between the super spreaders and the general population, the initial logarithmic derivative of the general population is still dominated by the influence of the super spreaders. with a simple coupled model of a small super spreader population within a general population, we can obtain the qualitative characteristics of the a priori puzzling evolution of the logarithmic derivative of proxies of the covid- epidemic evolution as found in several countries. indeed, the dynamics of this epidemic seems paradoxical at first sight, when interpreted in the frame of a simple sir model: the very high apparent r derived from the extremely fast doubling times of the epidemic would hint at a huge peak, and a necessary herd immunity which would be above % of the population. given the cfr of the order of %, that has lead to predictions of large numbers of death. but the epidemic seems to have a quickly diminishing logarithmic derivative of most of its proxies, be it hospital admissions or deceased patients, while at the same time absolutely not reaching anything near herd immunity. of course, one may think that this is due to the policies put into place. but the differences in policies put in place, and the universality of this observed dynamics may raise questions as to the influence of these policies versus the dynamics of this epidemic. the coupling between a super spreader group that does reach herd immunity and the larger population can qualitatively explain such a phenomenon. if the covid- . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . dynamics has such a kind of phenomenon as a basis, then the dynamics seems to be quite independent of any non-pharmaceutical measures taken. the model calculations show that even if the policies do have influences on the β parameters, these influences don't modify strongly the overall behaviour. if the overall population had already an r significantly smaller than , then all policies decreasing this value even further don't have much effect on the outcome: it is only if the initial r is very close to that they might have a effect. if measures diminish the coupling β c between the overall population and the super spreader cohort, then the effect will be significant, though. finally if the measures diminish β in the spreader cohort, this will only spread out the whole dynamics in time, but it will not affect much the end result. this may explain why there seems to be a universal behaviour to the epidemic, quite insensitive to specific policies that try to diminish the β factors without having a very strong effect on β c , the only parameter that seems to have a proportional influence on the outcome. the coupled dynamics of a super spreader cohort within a general population that isn't critical is quite robust against non-pharmaceutical measures. but even in a general population that is slightly critical, a small group of super spreaders will dominate the behaviour in the beginning of the epidemic. the only difference is that the value of the logarithmic derivative is slightly positive after a while, instead of taking on a negative value. it might be that brazil is in this case. the model of a population in which the disease cannot propagate epidemically or would give rise to a very slightly propagating epidemic with an r value near one, in which a strongly coupled, but small, super spreader cohort is present in which the disease is strongly epidemic (large r value in that group) will have a robust dynamics that resembles the one observed of the covid- pandemic, displaying a very high initial logarithmic derivatives, decreasing steadily towards a small value. this dynamics is quite robust against non-pharmaceutical measures that modify the individual β values of this model. full lockdown policies in western europe countries have no evident impacts on the covid- epidemic key: cord- - x qf yu authors: bin, sheng; sun, gengxin; chen, chih-cheng title: spread of infectious disease modeling and analysis of different factors on spread of infectious disease based on cellular automata date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: x qf yu infectious diseases are an important cause of human death. the study of the pathogenesis, spread regularity, and development trend of infectious diseases not only provides a theoretical basis for future research on infectious diseases, but also has practical guiding significance for the prevention and control of their spread. in this paper, a controlled differential equation and an objective function of infectious diseases were established by mathematical modeling. based on cellular automata theory and a compartmental model, the slirds (susceptible-latent-infected-recovered-dead-susceptible) model was constructed, a model which can better reflect the actual infectious process of infectious diseases. considering the spread of disease in different populations, the model combines population density, sex ratio, and age structure to set the evolution rules of the model. finally, on the basis of the slirds model, the complex spread process of pandemic influenza a (h n ) was simulated. the simulation results are similar to the macroscopic characteristics of pandemic influenza a (h n ) in real life, thus the accuracy and rationality of the slirds model are confirmed. infectious diseases are diseases that can be transmitted from person to person, from person to animal, or from animal to animal after proto-microorganisms and parasites infect human beings or animals [ ] [ ] [ ] . infectivity, epidemic, and uncertainty are the three main characteristics of infectious diseases. a thorough study of the spread causes, spread routes, spread processes, and epidemic laws of infectious diseases is the main method for effective prevention, control, and elimination of infectious diseases. at present, the mathematical study of infectious diseases is mainly based on the theory and method of infectious disease dynamics [ ] [ ] [ ] . the essence of infectious disease dynamics is to establish a mathematical model that can reflect the spread process, spread law, and spread trend of infectious diseases. its advantage is that, according to the characteristics of infectious diseases, the model of infectious diseases is reasonably assumed, the appropriate parameters are set, and the appropriate variables are selected. then, the dynamic characteristics of infectious diseases can be clearly revealed. it has laid a solid foundation for further analysis of the causes and key factors of the spread of infectious diseases, and for seeking the optimal strategies for the prevention and control of such diseases. the main method to study and forecast the spread mechanism of infectious diseases is to establish mathematical models. some of these are used to study the general laws of infectious diseases, while others are used to study specific infectious diseases, such as hfmd (hand foot and mouth disease), tuberculosis, aids, and so on. in , bernoulli [ ] began using mathematical models to study the spread of smallpox by vaccination. in , hamer [ ] constructed and analyzed a discrete time model for the study of recurrent measles epidemics. in , kermack and mckendrick [ ] proposed the sir (susceptible-infected-recovered) compartmental model for the first time in order to study the epidemic law of the black death prevailing in europe at that time. on the basis of the sir model's analysis, the "threshold theory" was proposed to distinguish the spread or regression of the disease. the validity of the sir model has been proven by the data regarding large-scale infectious diseases in history, thus the deterministic model [ ] based on a differential equation has been widely accepted. with the deepening of research, the factors involved in establishing the mathematical model are increasing, and the dimension of the model is also increasing. based on the classical sir model, aron and schwartz [ ] proposed the seir(susceptible-exposed-infective-recovered) model in . that model considers that the latency of infectious diseases also has an impact on infectious diseases, so the model is more realistic. focusing on severe acute respiratory syndrome (sars) infectious disease spread in recent years, safi and gumel [ ] constructed the seqijr(susceptible-exposed-quarantine-infective-isolation-recovered) model according to the characteristics of sars. small and chi [ ] studied the effects of vaccination and isolation on the sars epidemic and constructed the seirp (susceptible-exposed-infective-recovered-persevered) model. in addition, some researchers start with the population structure of infectious disease spread and study the spread model of infectious disease. according to the influence of age on the spread of infectious diseases, boklund et al. [ ] proposed a model to better characterize the effect of age heterogeneity on the spread of infectious diseases. according to the difference in population, meng et al. [ ] divided the population into different groups, and they proved the global stability of disease-free equilibrium and endemic equilibrium. with the development of artificial intelligence, the network dynamics model has gradually become a new research method of infectious disease model. the most common network dynamics models include the ordinary differential equation model, the discrete differential equation model, the impulsive differential equation model, and the differential equation model with time delay. the main methods are finite equation theory, matrix theory, bifurcation theory, k-order monotone system theory, central manifold theory, lasalle invariant principle, etc. however, these research methods are all theoretical studies on infectious diseases, but it is difficult to apply them to practical problems. the concept of cellular automata was proposed in the s. cellular automata can be described as a dynamic system consisting of a transformation function in cellular space, which is discrete in time and space. the cellular automata model can be formally expressed as ca = (l c , s, m, f ), where ca represents the cellular automaton system, l c represents the mesh space which is divided according to given rules, a mesh corresponding to a cell of cellular automata, s represents the set of cell states, m = (c , c , . . . , c n ) represents the set of current cell adjacent to cells, and f represents the transformation function which can transform c n to c, the function that can calculate the state of cell c at t + time according to the state of adjacent cells of cell c at t time. adjacent cells are moore neighbors with radius = . as shown in figure , cells can move in eight directions. misra et al. [ ] gave a comprehensive introduction to the theory and application of cellular automata. since the s, epidemic spread models based on cellular automata [ ] [ ] [ ] [ ] have been extensively studied. according to the characteristics and mechanism of aids, pan et al. [ ] proposed a spread model of aids based on cellular automata. lópez et al. [ ] proposed an epidemic spread misra et al. [ ] gave a comprehensive introduction to the theory and application of cellular automata. since the s, epidemic spread models based on cellular automata [ ] [ ] [ ] [ ] have been extensively studied. according to the characteristics and mechanism of aids, pan et al. [ ] proposed a spread model of aids based on cellular automata. lópez et al. [ ] proposed an epidemic spread model based on cellular automata that considers individual heterogeneity, population mobility ratio, and individual maximum moving distance. because cellular automata can perform some experiments that cannot be done in real life by modeling, we can analyze the actual situation and obtain the results, in order to solve the complex problems that cannot be dealt with in the deterministic model. it is thus becoming a typical representative of the network dynamics model. based on the ability of cellular automata to model complex problems, this paper considered that, in real society, population mobility is caused by economic development, living environment, education level, and other factors, and that population density, sex ratio, and age structure of area also have some influence on the spread of infectious diseases. an epidemic spread model susceptible-latent-infected-recovered-dead-susceptible (slirds) based on cellular automata was therefore established. the contributions of our research are as follows: • a more realistic epidemic spread model based on cellular automata was established and achieved good results in simulation experiments. the effects of population density, sex ratio, and age structure on the spread of infectious diseases were discussed, and the simulation results were analyzed to observe the effects of the above three factors on the spread process of infectious diseases. the suggestions given in this paper based on the three influencing factors provided strong support for researchers to study the spread process of infectious diseases in different environments. the rest of this paper is organized as follows. the methodology of our research is introduced in section . simulation results and analysis are given in section . discussions are presented in section . finally, conclusions are given in section . on the basis of the sir and sis (susceptible-infected-susceptible) models, the state of the population was divided into susceptible, latent, infected, recovered, and dead. the total number of members of the population is denoted as n(t). s(t) represents susceptible population, meaning the number of members of the population who are not infected but are susceptible to infection at time t. latent population is denoted as l(t), meaning the number of members of the population infected at time t but not yet affected, and at this time the individual is not infectious. infected population is denoted as i(t), meaning the number of members of the population who are infected and have infectivity at time t. recovered population is denoted as r(t), meaning the number of members of the population who are immune at t time and will not be infected for a certain period of time. dead population is denoted as d(t), meaning the number of members of the population who died of infectious diseases at time t, and individuals are not infectious at the moment. the slirds model can be described through the following differential equation models: where δ represents the proportion of the population who lost immunity to the infectious disease, β is the ratio coefficient of the infection rate, ω is the latency ratio coefficient of the infectious disease, γ is the ratio coefficient of the recovered infected population, and i o and s o represent the ratio of infected and susceptible individuals in the initial population, respectively. the transition relationships of states in the slirds model are shown in figure . where represents the proportion of the population who lost immunity to the infectious disease, is the ratio coefficient of the infection rate, ω is the latency ratio coefficient of the infectious disease, is the ratio coefficient of the recovered infected population, and and represent the ratio of infected and susceptible individuals in the initial population, respectively. the transition relationships of states in the slirds model are shown in figure . in order to simulate the phenomenon of crowd movement in the real world, this paper introduced the idea of random walk cellular automata to simulate individual movement in the crowd. considering the limitation of individual movement, the maximum step length l is set for individual movement. at the same time, considering the individual activity m, all individuals are scanned randomly in each time step, and the individuals whose proportion is m are selected. and ( | |, ≤ ) are chosen randomly for each selected individual ( , ) , and then ( , ) and ( , ) are exchanged to complete the individual movement. in this paper, the slirds epidemic model based on cellular automata is proposed. assuming that the environment of the crowd is a regular = × mesh space, a sparse matrix whose density is = ⁄ ( is the set of individuals) is generated randomly. each non-zero element of the matrix represents an effective individual. represents the neighbor set of cellular nodes, and it uses a moore neighbor with radius = . ( , ) ( ) = , , , , is used to represent the cell state in the i-th row and the j-th column at time t. different values represent different states as follows: in order to simulate the phenomenon of crowd movement in the real world, this paper introduced the idea of random walk cellular automata to simulate individual movement in the crowd. considering the limitation of individual movement, the maximum step length l is set for individual movement. at the same time, considering the individual activity m, all individuals are scanned randomly in each time step, and the individuals whose proportion is m are selected. d i and d j (|d i |, d j ≤ l) are chosen randomly for each selected individual c (i,j) , and then c (i,j) and c (i+d i ,j+d j ) are exchanged to complete the individual movement. in this paper, the slirds epidemic model based on cellular automata is proposed. assuming that the environment of the crowd is a regular n = n × n mesh space, a sparse matrix whose density is ρ = c n /n (c n is the set of individuals) is generated randomly. each non-zero element of the matrix represents an effective individual. m represents the neighbor set of cellular nodes, and it uses a moore neighbor with radius = . s (i,j) (t) = { , , , , } is used to represent the cell state in the i-th row and the j-th column at time t. different values represent different states as follows: s (i,j) (t) = represents susceptible state, meaning that individuals are not infected and they are immune to this infectious disease; s (i,j) (t) = represents latent state, meaning that individuals have been infected, but they do not have infectivity; s (i,j) (t) = represents infected state, meaning that individuals are infected and infectious; s (i,j) (t) = represents recovered state, meaning that individuals have recovered and acquired immunity within a certain period of time; s (i,j) (t) = represents dead state, meaning that individuals are dead and they do not have infectivity. because cellular automata cannot reflect every individual's and their neighbors' randomness, unified parameters t , t , and t are introduced, t representing the maximum peak of latency time for each individual, t representing the maximum peak of illness time for each individual, and t representing the maximum peak of immunization time for each individual. t s (i,j) (t) represents latency time of the individual, t s (i,j) (t) represents illness time of the individual, and t s (i,j) (t) represents immunization time of the individual. because of heterogeneity among individuals, each individual shows different resistance, infectivity, and infectious range to disease. this paper considers the effects of population density, sex ratio, and age structure on infectious disease spread in the population, and discusses the influence of different factors on infectious disease spread. in real life, because there are differences in climate, economy, education, and medical treatment, the population is not divided by rules like cellular automata. for example, in china, the population density in the southeast coastal areas is greater than that in the northwest. in addition, because of the different distribution of business districts, schools, and hospitals, the distribution of population in the same city is not uniform. in areas with a large population density, the distance between individuals is shorter and the spread range of individuals is wider. individuals in the population have higher contact frequency and more neighbors around them, so their infectivity and the probability of being infected also increase. in order to study and analyze the influence of population density on infectious disease spread, each individual is mapped into a cell in the cellular automata model. when there is no individual and the individual is in dead state in a cell, they are not infectious. in order to simulate the difference in population density, the population density can be simulated by setting the value of d(t) in the initial state. at this time, d(t) does not represent the number of dead individuals, but represents that there is no individual in the cell. in this paper, a sparse matrix was used to simulate the random distribution of population and the infectious disease spread, and then the trend of infectious disease spread under different population densities as well as the influence of different population densities on infectious disease spread were analyzed. due to the influence of economic development and other factors, the population ratio and age structure in different regions are also different. for example, young and middle-aged people in remote mountainous areas go to work in big cities, resulting in a large number of old and young people in the original area. in areas where labor is scarce, such as coal mines and crude oil mining areas, there is an imbalance in the proportion of men to women. therefore, it is of great practical significance to study the influence of sex ratio and age structure on infectious disease spread. in real life, because of different living environments, living habits, resistance levels to viruses, infectious abilities to diseases, levels of drug resistance, and spread ranges, and in order to simulate the spread mechanism of infectious diseases more accurately, it is particularly important to consider individual heterogeneity, establish an infectious disease spread model, and further analyze and predict the spread mechanism of the epidemic situation. in this paper, the probability of infection p (i,j) (t) was used to describe individual heterogeneity. individual heterogeneity is determined by the individual's resistance to disease and the infectivity of neighbor cells. the state of neighbor cells of cell c (i,j) at (i, j) can be expressed by an adjacency matrix as follows: after three times spread, its adjacency matrix is defined as follows: the infection rate of cell c (i,j) at time t is defined as follows: because the probability of infection is inversely proportional to one's own resistance, it is proportional to the infectivity of one's neighbors. thus, it can be expressed as follows: where f c (i,j) ,c(k,l) represents the infectivity of cell c (k,l) to cell c (i,j) (because of the difference in the constitution of different individuals, they have different infectivity and resistance) and f c (i,j) ,c(k,l) obeys ( , ) uniform distribution [ ] . r c (i,j) represents the infectious disease resistance of cell c (i,j) . some diseases have different influences on different sex and age groups, that is, individual sex and age differences are also important factors affecting an individual's resistance to disease. thus, it can be expressed as follows: where g m and g f represent the proportion of males and females in the population, f m and f f represent the influence coefficient of infectious diseases on males and females, y , . . . , y n are the proportion of various age groups in the population, f , . . . , f n are the influence coefficient of infectious diseases on n groups of populations, and t c (i,j) obeys ( , ) uniform distribution [ ] . the infection probability of each individual is determined by its own resistance to infectious diseases and the infectivity of its neighbors. at each time step, the individual state is updated synchronously. according to a given population density, the sparse matrix is generated to simulate the distribution of population, and then through the age structure and sex ratio, each individual sets their attribute values. the initial state of all individuals is set to s = , the state of the infected individuals is set to s = . individuals in cells are updated according to the following rules: ( ) when s (i,j) (t) = , individual infection probability p (i,j) (t) is calculated, and then whether the individual will be transformed into s (i,j) (t) = is determined. otherwise, s (i,j) (t) = . meanwhile, individual latency time t s (i,j) (t) = t s (i,j) (t) + . ( ) when s (i,j) (t) = , when t s (i,j) (t) < t , s (i,j) (t + ) = . otherwise, s (i,j) (t + ) = . meanwhile, individual illness time t s (i,j) (t) = t s (i,j) (t) + . ( ) when s (i,j) (t) = , when t s (i,j) (t) < t , s (i,j) (t + ) = . otherwise, the individual enters into dead state with probability λ, and s (i,j) (t + ) = ; the rest of individuals have recovered and acquired immunity, and s (i,j) (t + ) = . meanwhile, individual immunization time t s (i,j) (t) = t s (i,j) (t) + . ( ) when s (i,j) (t) = , when t s (i,j) (t) ≥ t , individual immunity to the infectious disease disappears with probability δ. the individual then turns into susceptible state, s (i,j) (t) = . ( ) at each time step, all individuals move. without considering other factors, this paper focused on the influence of three factors, namely, population density, individual heterogeneity, and mobility on infectious disease spread, and the slirds model based on cellular automata was constructed. in order to verify the validity of the model, this paper took pandemic influenza a (h n ) as an example to simulate the spread process of pandemic influenza a (h n ). in this paper, we used matlab simulation software (r b, mathworks, natick, ma, usa) to carry out simulation experiments; the simulated curves are realizations of the average from all simulations. according to the latent and infectious characteristics of pandemic influenza a (h n ), the time step of simulation is in days, and the total time is set to t = . the simulated initial number of members of the infected population was consistent with the actual number of members of the infected population, and we assumed that the proportion of the initial latent population was . %. first, the number of members of the infected population in the slirds model simulation experiments was compared with the actual data of pandemic influenza a (h n ) in beijing in mainland china (june-july ) [ ] . the comparison results are shown in figure . ( ) when ( , ) ( ) = , when ( ( , ) ( )) < , ( , ) ( + ) = . otherwise, ( , ) ( + ) = . meanwhile, individual illness time ( ( , ) ( )) = ( ( , ) ( )) + . ( ) when ( , ) ( ) = , when ( ( , ) ( )) < , ( , ) ( + ) = . otherwise, the individual enters into dead state with probability , and ( , ) ( + ) = ; the rest of individuals have recovered and acquired immunity, and ( , ) ( + ) = . meanwhile, individual immunization time ( ( , ) ( )) = ( ( , ) ( )) + . ( ) when ( , ) ( ) = , when ( ( , ) ( )) ≥ , individual immunity to the infectious disease disappears with probability . the individual then turns into susceptible state, ( , ) ( ) = . ( ) at each time step, all individuals move. without considering other factors, this paper focused on the influence of three factors, namely, population density, individual heterogeneity, and mobility on infectious disease spread, and the slirds model based on cellular automata was constructed. in order to verify the validity of the model, this paper took pandemic influenza a (h n ) as an example to simulate the spread process of pandemic influenza a (h n ). in this paper, we used matlab simulation software (r b, mathworks, natick, ma, usa) to carry out simulation experiments; the simulated curves are realizations of the average from all simulations. according to the latent and infectious characteristics of pandemic influenza a (h n ), the time step of simulation is in days, and the total time is set to t = . the simulated initial number of members of the infected population was consistent with the actual number of members of the infected population, and we assumed that the proportion of the initial latent population was . %. first, the number of members of the infected population in the slirds model simulation experiments was compared with the actual data of pandemic influenza a (h n ) in beijing in mainland china (june-july ) [ ] . the comparison results are shown in figure . in figure , the abscissa is the time step of simulation and the ordinate is the number of infected individuals. the correlation coefficient of the two sets of data is . by t-test. it shows that the simulation results are close to the actual data and that the model is reasonable and effective. in figure , the abscissa is the time step of simulation and the ordinate is the number of infected individuals. the correlation coefficient of the two sets of data is . by t-test. it shows that the simulation results are close to the actual data and that the model is reasonable and effective. all things being equal, the parameters of two simulations for the slirds model were set as follows: in figure , considering the difference in population base, the number of members of the population that died, were susceptible, were infected, and were immunized was replaced by death, susceptibility, infection and immunization rates to describe the changes in population in different states. from the death rate curve in figure a , it can be seen that the death rate increases with the increase in figure , considering the difference in population base, the number of members of the population that died, were susceptible, were infected, and were immunized was replaced by death, susceptibility, infection and immunization rates to describe the changes in population in different states. from the death rate curve in figure a , it can be seen that the death rate increases with the increase of population density, but the overall trend is rising and tending to be stable. from the susceptibility rate curve in figure b , it can be seen that the change in population density has little influence on the susceptible population, and the susceptibility will first decrease and then reach a stable value when the population density is large. from the infection rate curve in figure c , it can be seen that the change in population density has little influence on the infected population. when the population density is large, the number of members of the infected population is greater, but the general trend is rising first, then falling, and finally tends to be stable. from the immunization rate curve in figure d , it can be seen that the change in population density has little influence on the immune population. when the population density is large, the immunity first rises and then reaches a stable value. according to the above analysis, it is known that when the population density is large, the spread rate of infectious diseases is faster. all things being equal, the ratio of males to females was : . the parameters of two simulations for the slirds model were set as follows: ( ) the influence coefficients of infectious disease on males and females were . and . , respectively. ( ) the influence coefficients of infectious disease on males and females were . and . , respectively. two simulation results are shown in figure . as shown in figure a , we can see that when infectious diseases have a greater influence on males, the number of deaths is higher, but the overall trend is rising and gradually stable. as shown in figure b , we can see that infectious diseases have less influence on susceptible population under different influence coefficients; when infectious diseases have a greater influence on females, the number of members of the susceptible population first decreases and then reaches a stable value. as shown in figure c , we can see that infectious diseases have less influence on infected population under different influence coefficients; when infectious diseases have a greater influence on males, the number of members of the susceptible population first decreases and then reaches a stable value. however, the overall trend is first rising and then falling, and finally tends to be stable. as shown in figure d , we can see that infectious diseases have less influence on recovered population under different influence coefficients; when infectious diseases have greater influence on males, the number of members of the susceptible population increases first, and then reaches a stable value. according to the above analysis, it is known that in cities with more males than females, when the infectious disease has a great influence on males, infectious diseases have a greater influence on the population because of the large population base of males. similarly, there are corresponding phenomena in cities with more females than males. ( ) the influence coefficients of infectious disease on males and females were . and . , respectively. ( ) the influence coefficients of infectious disease on males and females were . and . , respectively. two simulation results are shown in figure . as shown in figure a , we can see that when infectious diseases have a greater influence on males, the number of deaths is higher, but the overall trend is rising and gradually stable. as shown in figure b , we can see that infectious diseases have less influence on susceptible population under different influence coefficients; when infectious diseases have a greater influence on females, the number of members of the susceptible population first decreases and then reaches a stable according to related materials [ ] , the influence coefficient of pandemic influenza a (h n ) on males and females is very different. in simulation experiments, the influence coefficients of pandemic influenza a (h n ) on males and females were set to g m = . , g f = . , respectively. the parameters of two simulations for the slirds model were set as follows: ( ) the ratio of males to females is : . ( ) the ratio of males to females is : . two simulation results are shown in figure . from the death curve in figure a , we can see that when the number of males is large, the number of deaths is higher, but the overall trend is rising and gradually stable. from the susceptibility curve in figure b , we can see that under different sex ratios, infectious diseases have little influence on susceptible population. when the number of females is large, the number of members of the susceptible population first decreases and then reaches a stable value. from the infection curve in figure c , we can see that under different sex ratios, infectious diseases have little influence on the infected population. when the number of males is large, the number of members of the infected population decreases first and then reaches a stable value. from the immunization curve in figure d , we can see that under different sex ratios, infectious diseases have little influence on the immunization population. when the number of males is large, the number of members of the immunization population increases first, and then reaches a stable value. according to related materials [ ] , the influence coefficient of pandemic influenza a (h n ) on males and females is very different. in simulation experiments, the influence coefficients of pandemic influenza a (h n ) on males and females were set to = . , = . , respectively. the parameters of two simulations for the slirds model were set as follows: ( ) the ratio of males to females is : . ( ) the ratio of males to females is : . two simulation results are shown in figure . from the death curve in figure a , we can see that when the number of males is large, the number of deaths is higher, but the overall trend is rising and gradually stable. from the susceptibility curve in figure b , we can see that under different sex ratios, infectious diseases have little influence on susceptible population. when the number of females is large, the number of members of the susceptible population first decreases and then reaches a stable value. from the infection curve in figure c , we can see that under different sex ratios, infectious diseases have little influence on the infected population. when the number of males is large, the number of members of the infected population decreases first and then reaches a stable value. from the immunization curve in figure d , we can see that under different sex ratios, infectious diseases have little influence on the immunization population. when the number of males is large, the number of members of the immunization population increases first, and then reaches a stable value. according to the above analysis, it is known that when the number of males is larger in the cities where infectious diseases affect men more, infectious diseases have a greater influence on the population. due to factors such as mobility and spatial environment, age structure of the population presents different distributions. the age structure of a city can be divided into three types: young, adult, and aged according to the proportion of children, adolescents, youth, middle-aged people, and elderly people. according to the above analysis, it is known that when the number of males is larger in the cities where infectious diseases affect men more, infectious diseases have a greater influence on the population. due to factors such as mobility and spatial environment, age structure of the population presents different distributions. the age structure of a city can be divided into three types: young, adult, and aged according to the proportion of children, adolescents, youth, middle-aged people, and elderly people. according to related materials [ ] , the influence coefficient of pandemic influenza a (h n ) on children, adolescents, youth, middle-aged people, and elderly people is very different. in simulation experiments, the influence coefficients of pandemic influenza a (h n ) on children, adolescents, youth, middle-aged people, and elderly people were set to f = . , f = . , f = . , f = . , f = . , respectively. all things being equal, the parameters of three simulations for the slirds model were set as follows: figure . the death, susceptibility, infection, and immunization curves are shown in figure a -d, respectively. it can be seen that the number of deaths in the aged cities is the largest. the number of young urban deaths is only inferior to that of the aged cities, whereas the number of deaths in the adult cities is the least. however, the overall trend of change is gradually stable after rising for all types of cities. the difference in age structure of the population has little influence on the susceptible population, and the number of members of the susceptible population in adult cities decreases first and then reaches a stable value. the difference in age structure of the population has little influence on the infected population. the number of members of the infected population in the aged cities is the highest, but the general trend is rising first and then decreasing for all types of cities. the difference in age structure of the population has little influence on the immunization population, and the number of immune individuals in the adult city rises first to then reach a stable level. according to the above analysis, it is known that infectious diseases spread more slowly in adult cities than in aged and young cities, but the resistance of young cities to infectious diseases is slightly greater than that of aged cities. according to related materials [ ] , the influence coefficient of pandemic influenza a (h n ) on children, adolescents, youth, middle-aged people, and elderly people is very different. in simulation experiments, the influence coefficients of pandemic influenza a (h n ) on children, adolescents, youth, middle-aged people, and elderly people were set to = . , = . , = . , = . , = . , respectively. all things being equal, the parameters of three simulations for the slirds model were set as follows: ( figure . the death, susceptibility, infection, and immunization curves are shown in figure a -d, respectively. it can be seen that the number of deaths in the aged cities is the largest. the number of young urban deaths is only inferior to that of the aged cities, whereas the number of deaths in the adult cities is the least. however, the overall trend of change is gradually stable after rising for all types of cities. the difference in age structure of the population has little influence on the susceptible population, and the number of members of the susceptible population in adult cities decreases first and then reaches a stable value. the difference in age structure of the population has little influence on the infected population. the number of members of the infected population in the aged cities is the highest, but the general trend is rising first and then decreasing for all types of cities. the difference in age structure of the population has little influence on the immunization population, and the number of immune individuals in the adult city rises first to then reach a stable level. according to the above analysis, it is known that infectious diseases spread more slowly in adult cities than in aged and young cities, but the resistance of young cities to infectious diseases is slightly greater than that of aged cities. in this paper, we used the idea of a sparse matrix to add population density, sex ratio, and age structure factors into the slirds model. population density was set to and . , respectively. all things being equal, with the increase of population density, infectious diseases spread faster, and infectious diseases have a greater influence on the population. when analyzing the influence of sex ratio on the spread of infectious diseases, we considered two factors, namely, different influence coefficient and different sex ratio. first, the ratio of males to females was set to : . because of the large population base of males, infectious diseases have a greater influence on the population when the infection coefficient is greater. second, the influence coefficients of infectious diseases on males and females were . and . , respectively. because infectious diseases have a greater influence on males, when the number of males is larger, the influence of infectious diseases on the population is greater. when analyzing the influence of age structure on the spread of infectious diseases, we simulated three types of population distribution structure, namely, young, adult, and aged, according to the age structure distribution ratio. the number of members of the infected population and deaths in the aged cities were the largest, and the susceptibility of adult cities to infectious diseases was stronger. that is, the uniform distribution of age plays a more active role in the spread of infectious diseases. in order to effectively prevent the spread of infectious diseases in the population, we offer three suggestions according to the three influencing factors. ( ) population density: the regional economy should be balanced, the large-scale turnover of personnel should be reduced, the density of urban population should be controlled, the population in densely populated areas such as schools should be evacuated during the epidemic period of infectious diseases. ( ) sex ratio: when infectious disease has a greater influence on a certain sex, or if the sex ratio is larger in the population, attention should be paid to prevention and treatment with respect to that sex. ( ) age structure: the age structure should be optimized and the age structure of the city should be stabilized. on this basis, we should pay attention to prevention and treatment with respect to disadvantaged groups (such as the elderly and children) in the spread of infectious diseases. many factors affect the spread of infectious diseases. this paper only studied the influence of the above three factors on the spread of infectious diseases. the many factors that must be further explored in the future include the following: first, the influence of population activity on the spread of infectious diseases; second, the influence of population size on the spread of infectious diseases; and third, in view of the analysis of the influence factors, how to implement effective prevention and control measures against the spread of infectious diseases in specific cities. in order to study the main factors that affect the spread process of infectious diseases, the slirds model was proposed in this paper. combined with cellular automata, an epidemic model based on cellular automata was established. in the simulation experiment, the influence of population density, sex ratio, and age structure on infectious disease spread was analyzed by comparing the results with those from the actual spread process of pandemic influenza a (h n ), and the accuracy of the slirds model was confirmed. with research on the spread of infectious diseases, the advantage of using cellular automata to model complex problems can be used to optimize epidemic models. the system can better analyze the factors affecting the spread of infectious diseases, and provide better theoretical support for the prevention and control of infectious diseases. because cellular automata cannot reflect every individual's and their neighbors' randomness, there was a lack of individual randomness in the slirds model for the maximum peak of each state for the different durations. this will be the direction that we take in the future to focus on improvement. the mathematical theory of infectious diseases and its applications the mathematics of infectious diseases modelling the influence of human behaviour on the spread of infectious diseases: a review modeling infectious disease dynamics in the complex landscape of global health mathematical modeling of infectious disease dynamics effects of limited medical resource on a filippov infectious disease model induced by selection pressure une nouvelle analyse de la mortalite cause par la petite werole et desavantages de i' inoculation pour al prevenir epidemic disease in england contributions to the mathematical theory of epidemics router-level internet topology evolution model based on multi-subnet composited complex network model seasonality and period-doubling bifurcations in an epidemic model mathematical analysis of a disease transmission model with quarantine, isolation and an imperfect vaccine small world and scale free model of transmission of sars comparing the epidemiological and economic effects of control strategies against classical swine fever in denmark asymptotic stability of a two-group stochastic seir model with infinite delays cellular automata-theory and applications a simple model of recurrent epidemics the impact of the wavelet propagation distribution on seirs modeling with delay optimizing content dissemination in vehicular networks with radio heterogeneity a cellular automaton model for the transmission of chagas disease in heterogeneous landscape and host community a model research on aids diffusion based on cellular automaton addressing population heterogeneity and distribution in epidemics models using a cellular automata approach a heterogeneous cellular automata model for sars transmission the national legal report of infectious diseases from the year this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license author contributions: all authors contributed to the work in this paper. s.b., g.s., and c.-c.c. designed the research and wrote the paper. g.s. participated in the creation of the graphics.funding: this research was funded by the shandong provincial natural science foundation, china, grant number zr mg . the authors declare no conflict of interest. key: cord- -ekgqdjlk authors: anand, shuchi; montez-rath, maria; han, jialin; bozeman, julie; kerschmann, russell; beyer, paul; parsonnet, julie; chertow, glenn m title: prevalence of sars-cov- antibodies in a large nationwide sample of patients on dialysis in the usa: a cross-sectional study date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ekgqdjlk background: many patients receiving dialysis in the usa share the socioeconomic characteristics of underserved communities, and undergo routine monthly laboratory testing, facilitating a practical, unbiased, and repeatable assessment of severe acute respiratory syndrome coronavirus (sars-cov- ) seroprevalence. methods: for this cross-sectional study, in partnership with a central laboratory that receives samples from approximately dialysis facilities across the usa, we tested the remainder plasma of randomly selected adult patients receiving dialysis in july, , using a spike protein receptor binding domain total antibody chemiluminescence assay ( % sensitivity, · % specificity). we extracted data on age, sex, race and ethnicity, and residence and facility zip codes from the anonymised electronic health records, linking patient-level residence data with cumulative and daily cases and deaths per population and with nasal swab test positivity rates. we standardised prevalence estimates according to the overall us dialysis and adult population, and present estimates for four prespecified strata (age, sex, region, and race and ethnicity). findings: the sampled population had similar age, sex, and race and ethnicity distribution to the us dialysis population, with a higher proportion of older people, men, and people living in majority black and hispanic neighbourhoods than in the us adult population. seroprevalence of sars-cov- was · % ( % ci · – · ) in the sample, · % ( · – · ) when standardised to the us dialysis population, and · % ( · – · ) when standardised to the us adult population. when standardised to the us dialysis population, seroprevalence ranged from · % ( · – · ) in the west to · % ( · – · ) in the northeast. comparing seroprevalent and case counts per population, we found that · % ( · – · ) of seropositive patients were diagnosed. when compared with other measures of sars-cov- spread, seroprevalence correlated best with deaths per population (spearman's ρ= · ). residents of non-hispanic black and hispanic neighbourhoods experienced higher odds of seropositivity (odds ratio · [ % ci · – · ] and · [ · – · ], respectively) compared with residents of predominantly non-hispanic white neighbourhoods. residents of neighbourhoods in the highest population density quintile experienced increased odds of seropositivity ( · [ · – · ]) compared with residents of the lowest density quintile. county mobility restrictions that reduced workplace visits by at least % in early march, , were associated with lower odds of seropositivity in july, ( · [ · – · ]) when compared with a reduction of less than %. interpretation: during the first wave of the covid- pandemic, fewer than % of the us adult population formed antibodies against sars-cov- , and fewer than % of those with antibodies were diagnosed. public health efforts to limit sars-cov- spread need to especially target racial and ethnic minority and densely populated communities. funding: ascend clinical laboratories. severe acute respiratory syndrome coronavirus (sars-cov- ) virus stimulates a rapid antibody response in people with symptomatic - and asymptomatic , , infection. seroprevalence of sars-cov- antibodies in a population thus serves as a reasonable measure of exposure and spread. seroprevalence surveys in the usa, however, have been restricted to single hotspots [ ] [ ] [ ] or under-represented high-risk or vulnerable populations. , moreover, these studies face challenges to timely repetition and longitudinal follow-up, limiting their utility for surveillance. [ ] [ ] [ ] patients receiving dialysis might be considered an ideal sentinel population in which to study the evolution of the covid- public health crisis. patients receiving dialysis in the usa undergo routine monthly laboratory studies to gauge the effectiveness of therapy and to screen for associated complications. in haemodialysis, regular access to the bloodstream abrogates the need for phlebotomy to acquire blood samples. risk factors for acquisition of sars-cov- and for severe covid- , including advanced age, non-white race, poverty, and diabetes, are the rule rather than the exception in the us dialysis population. testing remainder plasma from monthly samples obtained for routine care of patients on dialysis for sars-cov- antibodies therefore represents a practical approach to a population-representative surveillance strat egy, informing risks faced by a susceptible population while ensuring representation from racial and ethnic minorities. in addition, seroprevalence surveys in patients receiving dialysis can be linked to patient-level and community-level data to enable evaluation and quantification of differences in sars-cov- prevalence by demographic and neighbourhood strata, and thus facilitate effective mitigation strategies targeting the highest-risk individuals and communities. in partnership with a commercial clinical laboratory, we tested seroprevalence of sars-cov- antibodies in a randomly selected representative sample of patients. our goal was to provide a nationwide estimate of exposure to sars-cov- during the first wave of covid- in the usa, up to july, , with stratification by region, age, sex, and race and ethnicity. we also harnessed population data on sars-cov- cases and deaths and percentage testing positive using nasal swab testing to assess how seroprevalence estimates correlated with other epidemiological measures of covid- incidence. finally, to inform preventive strategies for the high-risk dialysis population as well as the general population, we investigated communitylevel correlates for seropositivity. we did a cross-sectional analysis of adult (≥ years) patients undergoing monthly laboratory testing at ascend clinical using samples obtained for routine clinical care that otherwise would have been discarded. ascend clinical is a commercial clinical laboratory based in redwood city, california, that receives samples from a nationwide network of around dialysis facilities, serving approximately patients. we randomly selected patients from the patient list on june , , for seroprevalence testing to be done in july, , using implicit stratification by region, age, sex, and race and ethnicity followed by systematic sampling with fractional polynomials. after sample selection and processing, ascend clinical sent anonymised data on patient age, sex, race and ethnicity, and residence and facility zip codes to stanford university investigators for analyses. stanford university investigators further linked patient geographical information (zip code) to census data and publicly avail able covid- burden and community mobility data. the study received expedited approval from the stanford university of medicine institutional review board; informed consent was waived. we used the us food and drug administration-approved siemens healthineers sars-cov- spike protein receptor evidence before this study measuring the seroprevalence of severe acute respiratory syndrome coronavirus (sars-cov- ) antibodies provides a comprehensive assessment of its community spread. community seroprevalence surveys require considerable infrastructure and expense, and face implementation challenges during the covid- pandemic due to restricted outreach in the worstaffected communities. of the two largest seroprevalence surveys in the usa, one was limited only to new york state (n= ) and used convenience sampling at grocery stores. a second survey used remainder plasma from people visiting commercial laboratories in six cities (n= ), but lacked details on race and ethnicity and other community-level risk factors. we tested the remainder plasma of patients receiving dialysis throughout the usa, using a chemiluminescence assay with high sensitivity and specificity. to our knowledge, we provide the first nationally representative estimate of sars-cov- seroprevalence in the us dialysis and us adult population, and estimates for differences in seroprevalence by neighbourhood race and ethnicity, poverty, population density, and mobility restriction. we also evaluate which of the existing measures of covid- incidence most closely correlate with seroprevalence. most importantly, we show that as patients receiving dialysis have monthly blood draws, without fail and without bias, and are a population with increased representation of racial and ethnic minorities, repeated crosssectional analyses of seroprevalence within this sentinel population can be implemented as a practical and unbiased surveillance strategy in the usa. similar to data from other highly affected countries and regions (eg, spain and wuhan, china), despite the intense strain on resources and unprecedented excess mortality being experienced in the usa during the covid- pandemic, fewer than % of us adults had formed antibodies to sars-cov- as of july, . there was significant regional variation from less than % prevalence in the west to more than % in the northeast. public health efforts to curb the spread of the virus need to continue, with focus on some of the highest-risk communities that we identified, such as majority black and hispanic neighbourhoods, poorer neighbourhoods, and densely populated metropolitan areas. a surveillance strategy relying on monthly testing of remainder plasma of patients receiving dialysis can produce unbiased estimates of sars-cov- spread inclusive of hard-toreach, disadvantaged populations in the usa. such surveillance can inform disease trends, resource allocation, and effectiveness of community interventions during the covid- pandemic. binding domain (s rbd) total antibody (immunoglobulin) chemiluminescence assay, which has % sensitivity (≥ days after a positive pcr test) and · % specificity. we chose this assay on the basis of its emergency use authorization in june, , in the context that s rbd is also the target of vaccine development efforts. sample processing is detailed in the appendix (p ). we linked patient-level resi dence data with cumulative and daily cases and deaths per population as compiled on a county level by the center for systems science and engineering at johns hopkins university and with nasal swab test positivity rates, as compiled on a state level by the covid tracking project. for utah, we followed the utah department of health groupings of several smaller counties and extracted data directly. new york city data are not available by county within the johns hopkins university dataset; therefore, we directly extracted data from the new york city dashboard. for county-level mobility restrictions, we used google mobility data that report an average percentage change in the number of workplace visits over the period march - , , before the implementation of shelterin-place restrictions in the majority of the country. percentage changes in the google mobility data are indexed to a corresponding weekday (eg, tuesdays are matched to tuesdays) from jan to feb , . we also linked patient-level residence data with zip code tabulation area (zcta) data from the american community survey (acs) -year estimates to ascertain patient neighbourhood proportion living below the poverty level and race and ethnicity mix, and with american census bureau estimates to ascertain population density. we defined zcta majority race and ethnicity as hispanic, non-hispanic black, or non-hispanic white if the population in the zcta was at least % hispanic, non-hispanic black, or non-hispanic white, respectively; where this was not the case, if the hispanic and black population combined was at least % of the population, the zcta majority was defined as hispanic and black, otherwise as other. for urban versus rural zcta status, we used the rural urban commuting area codes by census tract, categorising a zcta as dense urban, metropolitan, micropolitan, or small town or rural area if more than % of the population in the zcta was living in one of these area codes. we assumed a nationwide prevalence of sars-cov- antibody of %. , to generate prevalence estimates for patients on dialysis using preselected regional strata with precision within · %, a sample of was required (appendix p ). based on previous trends, we expected % of selected samples to be unavailable in july, , due to death, move to other facilities, or other reasons for missing laboratory data (eg, hospitalisation or non-adherence). accounting for this potential dropout, we randomly selected patients. we present prevalence estimates with % cis in our sample, standardised to the us adult dialysis population and to the us adult population. for the us adult dialysis based on the test sensitivity range obtained by schnurra and colleagues in their external validation, we also provide test characteristic-adjusted sample population estimates, ranging sensitivity from % to %. to compute the percentage of estimated sero prevalent cases that were likely to be diagnosed cases, , we compared the estimated seroprevalent cases per adult population with johns hopkins university esti mates of cumulative diagnosed cases per us adult popu lation as of june , . to standardise estimates, we assigned weights to each person based on their membership to each of strata of census regions (northeast, south, midwest, and west), age ( - , - , - , and ≥ years), and sex. we defined post-stratification weights as the proportion of each stratum represented in the us dialysis population or us adult population divided by the analogous proportion in the sample. [ ] [ ] [ ] we then computed weighted frequencies and % cis according to four prespecified strata (region, age, sex, and race and ethnicity) with differences evaluated using rao-scott χ² tests. , due to the missingness of race and ethnicity data in the electronic health records, we used the additional measure of zcta race and ethnicity distribution with categories adapted from moore and colleages. , next, we correlated five measures of covid- incidence-cumulative cases on june , (or first available date between june and june , ); cumulative deaths on june , (or last available date between june and june , ); -day averages of daily cases and daily deaths; and percentage testing positive on nasal swab tests between june and june , -with sars-cov- seroprevalence in patients on dialysis in july, . to do this, we first collapsed all measures to a state level and then assessed the spearman's correlation coefficient ρ for the association of each measure with seroprevalence. because of the high density of ascend clinical facilities in new york, texas, and california, we also chose those states to present county-level correlations. finally, using logistic regression, we determined the age-adjusted and sex-adjusted correlates of seropositivity for patient zcta race and ethnicity distribution, percentage living below poverty level, rural or urban classification, population density, and county mobility restriction. we assumed statistical significance at α< · . all statistical analyses were done with sas enterprise guide (version . ) and stata (version . ). ascend clinical laboratories supported the remainder plasma testing for sars-cov- antibodies. sa, mm-r, and jh had complete access to all data in the study and sa, mm-r, jh, jp, and gmc were responsible for the decision to submit for publication. of the people selected for testing on june , , were tested in july, (figure ), with ( · %) tested in the first weeks (appendix p ). the sampling was representative of the us dialysis patient distribution by age, sex, race and ethnicity (when excluding patients without race and ethnicity data), and region, except sampled patients were less likely to be non-hispanic black (table ) . compared with the us adult population, our sampled patient population was older, had more men, and was more likely to be non-hispanic black and living in non-white neighbourhoods seroprevalence ranged from · % ( · - · ) to · % ( · - · ) in our sampled population (appendix p ). when standardised to the us dialysis population, seroprevalence was · % ( · - · ), with high regional variation in seroprevalence (ranging from · % [ · - · ] in the west to · % [ · - · ] in the northeast; table ). seroprevalence was similar by sex and modestly lower in people aged years or older compared with those aged - years (table ) . differences in seroprevalence by race and ethnicity were similar using both our patient-level (electronic health record) and neighbourhood-level (zcta majority race and ethnicity) measures, with non-hispanic black patients having the highest seropositivity, followed by hispanic patients, and non-hispanic white patients having the lowest. we estimated the sars-cov- standardised seroprevalence in the us population to be · % ( % ci · - · ; table ). based on the johns hopkins university cumulative case data as of june , , the prevalence of (nasal swab) diagnosed cases was per us adult population, compared with our estimate of seropositive people per population, meaning that · % ( · - · ) of sero positive people were diagnosed. using data from our sampled population, variation by state was high, ranging from · % in seven states to · % ( · - · ) in new york, with the highest regional variation occurring in the northeast (figure ; appendix pp - ). when comparing state seropreva lence against cumulative cases and deaths per population, deaths correlated best (ρ= · for cases vs · for deaths; figure ). the percentage of people testing positive by nasal swab test and -day average of daily deaths in the latter half of june, , showed a weaker correlation (ρ= · and · , respectively), whereas -day average of daily cases did not correlate with seroprevalence (ρ=− · ). on a county level in california, new york, and texas, there was even more heterogeneity in the correlation between seroprevalence and other disease measures (ρ≤ · for all correlations for all three states' county-level data; appendix p ). likelihood of sars-cov- seropositivity was lower among older people (odds ratio · [ % ci · - · ] for people aged years or older vs people aged - years), but did not differ by sex ( · [ · - · ] for women vs men). in age-adjusted and sex-adjusted models, neighbour hood racial and ethnic distribution, poverty level, dense urbanisation, population density, and percentage change in workplace visits in early march, , were all strongly associated with seropositivity ( figure ). in our analysis of seroprevalence of sars-cov- spike protein receptor binding antibodies from a nationwide representative sample of patients receiving dialysis, we find that despite the usa contemporaneously leading the world in the numbers of diagnosed cases, overall, fewer than % of us adults had evidence of seroconversion in july, . a vast majority of us adults, including people receiving dialysis who are among the highest risk for mortality upon contracting sars-cov- , do not have evidence of exposure or immune response. furthermore, we find increased likelihood of sars-cov- seropositivity in residents of predominantly black and hispanic neighbour hoods (two to three times higher), poorer areas (two times higher), and the most densely populated areas (ten times higher). early reduction in community mobility in march, , was associated with % lower likelihood of individual-level seroconversion by july that year. unlike most published estimates of sars-cov- seroprevalence from the usa, , , patients included in our study sample had antibodies measured from blood collected as part of routine medical care. thus, our prevalence estimates should not be subject to selection bias due to presence versus absence of symptoms, availability of testing materials, local or regional testing strategies, geography, income, educational attainment, language proficiency, immigration status, mobility, anxiety, fear, or other factors. moreover, since end-stage kidney disease qualifies affected patients for medicare insurance, and since end-stage kidney disease disproportionately affects black, hispanic, and other disadvantaged populations, , , we are able to determine-with a high level of precision-differences in seroprevalence among patient groups within and across regions of the usa. of the two larger seroprevalence surveys published from the usa thus far, one was confined to new york state (n= ), employed a convenience sampling technique at grocery stores, and relied on a microsphere immunoassay with lower sensitivity. the second, the centers for disease control and prevention (cdc) six sites study (n= ), used remainder plasma from people getting testing for undefined clinical indications, and did not have detailed sociodemographic information about the tested people. uncertainty exists as to whether seroprevalence estimates in the dialysis population can be extrapolated to the us population more broadly. a recent analysis of sars-cov- igg antibodies in two dialysis units in london, uk, reported seroprevalence of %, higher than in healthy blood donors ( %) but lower than in healthcare workers ( %) sampled within a similar time frame. our data might overestimate overall seroprevalence in , , , states in white were not included in the sample. the general population since patients on dialysis are disproportionately from racial and ethnic minorities; , for example, black americans have a nearly four-times higher risk of end-stage kidney disease than white americans. moreover, the process of undergoing incentre haemodialysis might include the use of public or non-public shared transportation to and from the facility, and - h of care delivered in indoor facilities. conversely, these data might underestimate overall seroprevalence in the general population. patients receiving dialysis are less likely to be employed and more likely to restrict their mobility and social activity due to advanced age and frailty; therefore, they might have fewer opportunities to acquire the infection, par ticularly from asymptomatic individuals. extrapolating from multiple prospective hepatitis b immunisation studiesin which - % of vaccinated patients receiving dialysis mounted a response compared with % or more people from the general population-patients receiving dialysis might mount a weaker immune response and thus be less likely to seroconvert. finally, patients receiving dialysis might have been more likely to die or have been hospitalised due to complications of sars-cov- infection. if so, these patients would not have been present for testing in the dialysis facilities, creating a survival bias and yielding lower estimates of exposure. nonetheless, the ten-times difference we observed between diagnosed cases per population and our estimates of seropositive people per has been similarly reported in studies from new york, the cdc six sites study, and in a population-representative analysis from geneva. thus, our findings comport with other seroprevalence estimates. we confirm that as in other studies from covid- hotspots, , , a minority of the population has evidence of exposure and immune response, and a vast majority, including people at high risk for mortality (ie, the population on dialysis), remain vulnerable. in fact, even if the seroprevalence estimates derived from the us dialysis population overestimated true seroprevalence in the overall us adult population, our data nonetheless support that fewer than % of the us population has seroconverted as of july, , and all variables are at a neighbourhood (ie, zcta) level, except for reduction in workplace visits, which is at a county level, and are modelled separately, accounting for age and sex. poverty level is defined as percentage of people living below the federal poverty level in the zcta. population density quintiles are derived from the zcta (median people per square mile [iqr - ]). reductions in workplace visits were measured during the first weeks of march, , compared with a baseline in january-february, . or=odds ratio. sars-cov- =severe acute respiratory syndrome coronavirus . zcta=zip code tabulation area. · ( · - · ) age-sex-adjusted or ( % ci, log scale) herd immunity remains out of reach, as has been the conclusion from large international surveys from the uk and spain, where intense outbreaks of covid- occurred during the spring and summer of . furthermore, the seroprevalence differences captured by region, age, sex, and community-level risk factors (ie, internal comparisons) are expected to be similar in the us dialysis and us general adult population. our study provides convincing evidence that the covid- pandemic has dramatically amplified existing health disparities. data from the cdc highlighting sars-cov- health disparities evaluate hospitalisations and deaths by race and ethnicity, , calling into question whether black and hispanic populations are experiencing more severe illness versus facing higher likelihoods of exposure. some us state dashboards also report higher cumulative cases among black and hispanic people compared with non-hispanic white people, but none have as precisely quantified differences on a national level. neighbourhood poverty and population density were also highly correlated with seroprevalence, with a possible threshold effect for population density, such that there was a ten-times higher risk in the highest density zctas (> people per square mile). population density is recognised as a crucial factor, driving the spread in metropolitan areas, in confined spaces (eg, the diamond princess cruise ship), large gatherings (eg, the new orleans' mardi gras), , and in populous regions across the world. rocklöv and sjödin suggest that the basic reproduction number (r ) of sars-cov- increases linearly with population density. our data also show slightly lower likelihood of seropositivity among older people, as was seen in a recent report from geneva and attributed to better adherence to physical distancing measures by the authors. a higher competing risk from hospitalisations or mortality after sars-cov- exposure might be a larger contributing factor in the observed lower seroprevalence in older compared with younger age groups. in addition to providing an overall estimate of sars-cov- seroprevalence and quantifying differences by patient and community characteristics, our study puts forth a viable surveillance strategy for sars-cov- spread in the usa. who and other experts , advocate for repeated cross-sectional analyses of seroprevalence as a disease tracking system able to most completely measure the true incidence of sars-cov- , since these can more likely capture incidence of exposure in both symptomatic and asymptomatic individuals. in fact, we observed substantial heterogeneity in the correlation between seroprevalence and other measures of sars-cov- that are currently being used-with the exception of deaths per , which are a late outcome -supporting the use of rapidly instituted seroprevalence surveys as a complementary surveillance tool. additional public health implications of seroprevalence surveys include assessing testing adequacy. for example, in states where the difference between seropositive and diagnosed cases is decreasing over time, testing capacity is likely to be increasing. furthermore, following seroconversion rates over time can presage hospitalisations and intensive care unit stays, since the time between exposure and seroconversion is relatively short (median days), and can therefore facilitate resource allocation. finally, as we show by assessing community mobility restrictions, seroprevalence surveys can measure the effects of interventions to treat or prevent infection with sars-cov- . repeated serological surveys, if done in a community setting, would require extensive resources and yet remain subject to selection bias. however recurring monthly testing of remainder plasma of randomly selected sets of people-as is practically feasible in patients receiving dialysis-can serve as a representative surveillance system in the usa, with minimal phlebotomy or infrastructure requirement, and as our data show, include traditionally under-represented and socially disadvantaged groups. this analysis has numerous strengths. we used a highly specific and sensitive immunoassay, one which has been robustly linked to sars-cov- exposure. , , , the study sample was highly representative of the us dialysis population and, as noted, we used remainder plasma from specimens used in routine clinical care. the sample size and sampling scheme allowed us to estimate with precision prevalence across several patient characteristics. moreover, linking to us census and other publicly available data sources assembled during the pandemic provides valuable context when considering the implications of these data to the general population. there are also several important limitations. as noted previously, it is plausible that seroprevalence estimates from the us dialysis population overestimate seroprevalence in the us adult population. we do not have patient-level data on symptoms nor nasal swab testing results, and thus cannot test whether the likelihood of seroconversion differs in patients receiving dialysis from generally healthy adults, although preliminary data from london, uk, suggest no differences. we also do not have patient-level data on health status, employment status, income, household size, living space, and other sociodemographic factors, and so relied on neighbourhood proxies for some of these domains. dialysis units are more often located in urban areas, and thus we have under-representation of rural areas. finally, while large, our study was designed for precise regional, not state-level or county-level, estimates. in conclusion, we present sars-cov- seroprevalence data in a broadly representative sample of patients receiving dialysis across the usa and show striking differences in seroprevalence by several patient characteristics, with higher seroprevalence in younger patients, black and hispanic patients, and patients living in poorer and majority-minority neighbourhoods. these data can help to inform surveillance and management strategies during the next phase of the pandemic. serial sampling of dialysis remainder plasma should be used to determine trends in disease prevalence and the effect of various strategies being implemented around the usa to reduce the burden of covid- on the general population. sa assisted with data cleaning and analysis planning, and manuscript writing. mm-r developed the analysis plan, generated census data tables, supervised data analysis, and contributed to manuscript writing. jh undertook data cleaning and analysis, including linkage to external data and figure generation, and contributed to manuscript writing. jb undertook sample processing and data preparation and contributed to manuscript writing. rk selected seroprevalence testing, supervised sample processing, and contributed to manuscript writing. pb co-conceived the study, secured seroprevalence testing, and supervised sample processing and data preparation. jp supervised the study analysis plan, identified relevant external data, contributed to data interpretation, and supervised manuscript writing. gmc co-conceived the study, supervised the study analysis plan, and co-wrote the manuscript. jb, rk and pb are employed by ascend clinical laboratories. gmc is on the board of directors of satellite healthcare, a not-for-profit dialysis organisation. all remaining authors declare no competing interests. de-identified cross-sectional data from the analysis can be made available after authors' review of request and might require compilation of specific categories (eg, at the older age groups) to protect patient privacy. prevalence of sars-cov- in spain (ene-covid): a nationwide, populationbased seroepidemiological study sars-cov- shedding and seroconversion among passengers quarantined after disembarking a cruise ship: a case series antibody responses to sars-cov- in patients with covid- clinical validity of serum antibodies to sars-cov- : a case-control study eua authorized serology test performance natural history of asymptomatic sars-cov- infection sars-cov- infections and serologic responses from a sample of us navy service members-uss theodore roosevelt seroprevalence of sars-cov- -specific antibodies among adults in covid- antibody seroprevalence in cumulative incidence and diagnosis of sars-cov- infection in new york 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geneva, switzerland (serocov-pop): a population-based study post-stratification or non-response adjustment? post stratification analysis of health surveys the analysis of categorical data from complex surveys: chi-squared tests for goodness of fit and independence in two-way tables on chi-squared tests for multiway contingency tables with cell properties estimated from survey data availability of recreational resources in minority and low socioeconomic status areas the intersection of neighborhood racial segregation, poverty, and urbanicity and its impact on food store availability in the united states a report from the brescia renal covid task force on the clinical characteristics and shortterm outcome of hemodialysis patients with sars-cov- infection neighborhood poverty and racial differences in esrd incidence low income, community poverty and risk of end stage renal disease high prevalence of asymptomatic covid- infection in hemodialysis patients detected using serologic screening white/black racial differences in risk of end-stage renal disease and death racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the united states employment among patients starting dialysis in the united states frailty, dialysis initiation, and mortality in end-stage renal disease review article: hepatitis b and dialysis seroprevalence of immunoglobulin m and g antibodies against sars-cov- in china antibody prevalence for sars-cov- in england following first peak of the pandemic: react study in , adults covidview: a weekly surveillance summary of us covid- activity comparison of weighted and unweighted population data to assess inequities in coronavirus disease deaths by race/ethnicity reported by the us centers for disease control and prevention covid- and african americans geographic differences in covid- cases, deaths, and incidence-united states population density and basic reproductive number of covid- across united states counties ethnic and regional variations in hospital mortality from covid- in brazil: a cross-sectional observational study high population densities catalyse the spread of covid- assessing the extent of sars-cov- circulation through serological studies risk factors associated with mortality among patients with covid- in intensive care units in evaluation of nucleocapsid and spike protein-based enzyme-linked immunosorbent assays for detecting antibodies against sars-cov- evaluation of sensitivity and specificity of commercially available sars-cov- antibody immunoassays ascend clinical laboratories supported the remainder plasma testing for sars-cov- antibodies. sa was supported by k dk . mm-r and gc are supported by national institutes of health niddk k dk . we thank martin gorfinkel (mountain view, ca, usa) for his feedback on sampling design. key: cord- -kt m authors: wise, a.l.; manolio, t.a. title: public and population health genomics date: - - journal: medical and health genomics doi: . /b - - - - . -x sha: doc_id: cord_uid: kt m public health seeks to improve health at a population level through interventions that increase the net health benefit to the population as a whole. advances in genomics knowledge and technologies can add to this endeavor, but also pose a challenge when faced with often conflicting public health (population) and genomic medicine (individual) perspectives. combining the fields of genomic, population, and social sciences, population genomics or public health genomics looks at the promotion of health and prevention of disease using genomic knowledge through the lens of populations rather than individuals. in this chapter we will survey the three major disciplines contributing to population genomics (genomics, population, and social sciences) and explore two cross-cutting issues: global health and population versus individual health, using specific examples from diseases such as asthma, colon cancer, and cystic fibrosis. population sciences such as epidemiology focus on studying whole populations rather than individuals. through studying environmental, genomic, and social factors that affect human health, population level interventions can be identified. the social sciences focus on studying society and human behavior through fields such as anthropology, economics, law, psychology, and sociology. the study of the ethical, legal, and social implications (elsi) of genomics plays an important role in applying genomics to population health. although the fields of population genomics and genomic medicine look to prevent or treat disease through different perspectives, they can act complementarily to enhance overall health outcomes for both individuals and populations at large. population genomics seeks to integrate knowledge from genomic, population, and social sciences to improve population health. the genomic sciences focus on studying whole genomes, such as the entire dna sequence making up the human genome. through studying genomics, genetic variants influencing human health can be identified. studies of particular genes can then further elucidate the function of genetic variants. the three major disciplines contributing to population genomics (genomics, population science, and social sciences) explore two cross-cutting issues: global health, and population versus individual health. this aspect of the emerging field of population genomics is discussed in this chapter using specific examples from diverse diseases such as breast cancer, colorectal cancer, bronchial asthma, crohn disease, alzheimer dementia, and cystic fibrosis. around one in nine women worldwide develop breast cancer during their lifetime. a family history of breast cancer along with ovarian cancer may be encountered in approximately % of the affected women. a number of disease-causing mutations in the two major genes, brca and brca , are now recorded worldwide. in addition, several variants may occur in - % of breast cancer cases; these variants are found in less than % of the general population [ ] . specific populations, such as those of ashkenazi jewish descent, have an increased incidence of brca or brca variants. two variants in brca and one in brca are found at a rate times higher in ashkenazi jews than in the general population [ , ] . for these reasons, family members of those with known brca / variants or those with a family history of breast cancer may be offered genetic testing. men with brca / variants are also at an increased risk of developing breast cancer [ , ] . thousands of variants have been discovered in brca and brca , yet only a minority have a known deleterious effect [ ] . genetic testing therefore has the possibility of finding a variant of unknown effect, for which the functional significance is unclear. one recent study found that % of women undergoing brca and brca testing receive an ambiguous test result because of the detection of a variant of unknown significance [ ] . thus although deleterious variants are known to increase the risk of developing breast cancer approximately fivefold, deciding how to react to variants of unknown effect can be challenging for all involved including both clinicians and patients [ ] . genomic information can be used clinically to inform disease risk, diagnosis, drug selection, and drug dosing. colorectal cancer provides a good example of an area where population level screening along with genomic medicine approaches are coming together to improve overall population health. over million individuals are diagnosed with colorectal cancer each year worldwide, accounting for approximately - % of cancer diagnoses in [ ] . it is the third leading cause of cancer-related death in the united states and the fourth worldwide [ , ] . in colorectal cancer, a patient's genomic information can be used to determine risk of inherited colorectal cancer syndromes, whether certain biological agents will work in specific patients, and what starting dose to use on specific chemotherapeutics. as many as - % of colorectal cancer cases have a family history of colorectal cancer (two or more firstdegree relatives with colorectal cancer), yet only - % have an established familial genetic syndrome with a known genetic variant [ , ] . of those with established familial genetic syndromes, approximately % will be diagnosed with lynch syndrome (including variants in the genes mlh , msh , msh , pms , and epcam) and % with familial adenomatous polyposis (including variants in apc and mutyh) [ ] . individuals with a family history of colorectal cancer have a two-to threefold greater risk of developing colorectal cancer than the general population and thus genetic testing for an individual with a known family history has substantial public health benefit [ ] . those with a known family history of colorectal cancer are also recommended for screening at younger ages, typically years younger than the onset of the youngest case in their family. genetic testing is also used to determine treatment options in colorectal cancer [ , ] (table . ) . for example, genetic variants that make kras constitutively active have been shown to provide resistance to monoclonal antibodies directed against the upstream epidermal growth factor receptor (egfr), because both are components of a cellular pathway leading to abnormal cell growth and cancer. thus cetuximab and panitumumab (anti-egfr antibodies) are given only to individuals with normally functioning kras, where blocking egfr can have an effect [ ] . pharmacogenomics can also be useful in determining drug dosage for colorectal cancer. for example, the fda recommends testing for ugt a variants when administering irinotecan, because individuals homozygous or heterozygous for the ugt a * allele are at increased risk of developing neutropenia and severe infections [ ] . individuals with inactivating ugt a variants are therefore recommended to be started at a lower dosage of irinotecan to reduce the risk of neutropenia [ ] . in addition to modifying drug dosing, pharmacogenomic information can also be used in drug selection to choose agents more likely to give a beneficial response based on a patient's genetically driven ability to metabolize them. for example, in patients of asian ancestry given carbamazepine (used to treat epilepsy and bipolar disorder) the hla-b* allele has been associated with stevens-johnson syndrome/toxic epidermal necrolysis, a life-threatening skin condition. this allele can be found in over % of the population in some regions in asia including hong kong, thailand, malaysia, and parts of the philippines, and is very rare in other populations outside asia [ ] (table . ). within populations of asian ancestry, there can also be great variation, such as is seen within china where the hla-b* allele prevalence varies from to %, depending upon ethnicity. thus the us food and drug population variation is an important consideration when studying common complex conditions that are influenced by multiple genetic, environmental, and social risk factors, such as bronchial asthma. over million individuals of all ages have asthma worldwide [ ] . prevalence estimates can vary greatly by ethnicity; however, from % to % [ ] . in the united states, prevalence ranges from approximately % in european americans to % in african americans and % in hispanic americans [ ] . within admixed populations, such as hispanic americans, even greater variation can be seen when populations are further substratified, with mexican american populations around %, whereas puerto rican populations are closer to % [ ] . genetic studies have shown that at least some of this variation is caused by differences in genetic variants, with - % of the variation in asthma heritability explained by genetic factors [ , ] . for example, variants in adam have been seen in european, african american, and some hispanic populations, but not in other european american, mexican, puerto rican, and korean populations, all of which found different variants in adam associated with asthma [ ] (fig. . ) . studying the interplay between environmental, genetic, and social risk factors is also critical to understanding the etiology of this complex disease. for example, the effect of air pollution on asthma case reports is modified by genetic factors as well, showing potential gene-environment interactions. a key measure of air pollution is pm , the concentration in parts per million of particulate matter μm in diameter or less, which can penetrate and irritate small airways. pm has been shown in multiple epidemiological studies to be an independent risk factor for increased respiratory symptoms including asthma [ ] [ ] [ ] [ ] [ ] . similarly variants in over genes have been associated with asthma in genome-wide association studies (gwass) [ , , ] . looking at the two risk factors together, however, reveals a potential gene-environment interaction where variants in gstp , sod , and nfe l , all related to oxidative stress pathways, were also associated with increased hospital admissions for asthma-related symptoms during days with high pm levels [ ] . genomics can also be used to help identify and better define environmental risk factors in population studies. for example, genomic data profiling the bacteria inhabiting the human gut, or gut microbiome, has revealed differences in the bacterial populations present in individuals with crohn disease (a form of inflammatory bowel disease) [ ] . the genomic signatures of the gut microbiome in patients with crohn disease shows some bacterial populations to be decreased, whereas others are more abundant [ ] [ ] [ ] [ ] . many genetic loci have also been associated with multiple phenotypes, as evidenced in the national human genome research institute catalog of published gwass [ , ] . (fig. . ). such pleiotropic genes (genes associated with multiple phenotypes) can present additional challenges when considering the elsi of returning genetic testing results. for example, variants in apoe are associated with multiple phenotypes, including alzheimer dementia, cholesterol level, coronary disease, c-reactive protein, hyperlipoproteinemia type iii, low-density lipoprotein level, macular degeneration, and response to statin therapy [ ] . the apoe*e variant in particular has been associated with increased risk for developing both alzheimer dementia and atherosclerosis along with a protective effect against developing macular degeneration [ ] . in many ways the family serves as an intermediary between individual-and population-level views of health. it is an important viewpoint that should be considered in population genomics, because genomic information is inherently relevant not only to the individual tested, but also to their family members with whom they share a large proportion of their genetic variants. how and with whom such familyrelated health information can or should be shared is an important consideration for advancing both individual and family health. the availability of genomic information is also blurring the line between population and individual level views of health. for example, genetic testing for cystic fibrosis spans population screening-based carrier, prenatal, and newborn tests to individualized genomic medicine-based diagnostic and pharmacogenomic testing for treatment selection. from the population screening perspective, genetic testing is offered to prospective parents of european decent and others who may be at increased risk of having a child affected by cystic fibrosis, because the prevalence of cystic fibrosis is highest in northern europe [ ] . over variants have been found in the cftr gene, but the functional significance of many is unknown, with the most common variant associated with cystic fibrosis being Δf [ ] . in , the fda approved ivacaftor, the first drug to treat a specific cystic fibrosis variant, g d in cftr [ , ] (table . ). the g d variant impairs the ability of the cftr channel to open [ , , ] . ivacaftor functions by increasing the likelihood of the cftr channel being open, improving chloride transport and restoring the function of the cftr gene [ ] [ ] [ ] . as the cost of genomic sequencing continues to drop and electronic health records improve, the cost of collecting and interpreting genomic data may fall below the cost of conducting individual genetic tests, further blurring the line between clinical and public health data. although all three of the population sciences contributing to population genomics work together, there are also some issues that more broadly span the field of population genomics and its relationship to medicine and public health. touched upon in many of the examples discussed, it is important to consider the broader implications of population genomics to global health and how population and individual level views of health can work together to improve health worldwide. cardiovascular disease is a leading cause of death worldwide, with over . million deaths from ischemic heart disease, stroke, or another form of cerebrovascular disease in , and is highly amenable to study using population genomics techniques [ ] . for example, adding rs genotyping to the framingham risk score improved its ability to determine individuals who would suffer later cardiovascular events independent of family history [ ] . such models can be used to screen populations to determine individuals at increased risk of disease and recommend further testing and individualized genomic medicine. whereas chronic conditions such as cardiovascular disease make up the majority of deaths in the developed world, infections are still a major health concern within developing countries and are equally amenable to study using population genomics. genomics has made possible the rapid identification of the organisms causing recent pandemic outbreaks including h n and severe acute respiratory syndrome, as well as identifying the source of foodborne illness. the availability of genomic sequence information on malaria parasites, mosquito vectors, and their human hosts are all being leveraged to produce more rapid diagnosis and better drugs, vaccines, and intervention strategies to fight malaria [ , ] . to maximize the benefit of population genomics advances to global health, it is also important to include multiple populations of diverse age, ethnicity, and gender in disease research. as evidenced by the example of asthma genomics, the prevalence of disease can be highly variable across ancestral groups and genetic variants often vary in incidence as well. thus although a single pathway may be implicated in disease across many populations, the most common variant in each population may lie in different genes or gene regions. local environmental and social factors that impact disease and population health should also be incorporated into studies of population genomics to produce the most complete picture of disease etiology. for example, the prevalence of type diabetes mellitus is increasing globally and has been associated with multiple genetic (more than genes to date), epigenetic (such as methylation or histone modification), environmental (such as diet), and social factors (such as exercise), all of which contribute to this complex disease [ ] . the prevalence of type diabetes mellitus varies by country from approximately - %, with risk alleles such as the c allele in rs decreasing in incidence from sub-saharan africa to asia (fig. . ) [ , ] . effects of other risk factors also vary across different populations, with the relative risk of type diabetes mellitus for each kg/m increase in body mass index; for example, being . in asian americans, . in hispanic americans, . in european americans, and . in african americans [ ] . in this chapter we have explored how the integration of genomic, population, and social sciences in population genomics can improve health through examples in pharmacogenomics, population variation, and genetic pleiotropy. we have also investigated cross cutting issues in global health and population versus individual health where population genomics can play a crucial role in the translation of genomic health discoveries worldwide and population screening can work together with genomic medicine to provide the greatest health benefit to both individuals and populations at large. thus, multidisciplinary research in population genomics, can improve clinical care through understanding of the genetic variation in populations that contributes to complex disease. proceedings of the international consensus conference on breast cancer risk the risk of cancer associated with specific mutations of brca and brca among ashkenazi jews prevalence and penetrance of brca and brca gene mutations in unselected 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million participants type diabetes risk alleles demonstrate extreme directional differentiation among human populations, compared to other diseases ethnicity, obesity, and risk of type diabetes in women: a -year follow-up study allele frequency net: a database and online repository for immune gene frequencies in worldwide populations worldwide human relationships inferred from genome-wide patterns of variation adam polymorphisms and phenotype associations in childhood asthma association of adam polymorphisms with childhood asthma in a northern chinese population association of the adam gene with asthma and bronchial hyperresponsiveness key: cord- - tax ajw authors: bhopal, raj s. title: covid- zugzwang: potential public health moves towards population (herd) immunity date: - - journal: nan doi: . /j.puhip. . sha: doc_id: cord_uid: tax ajw summary covid- is pandemic, and likely to become endemic, possibly returning with greater virulence. outlining potential public health actions, including hygiene measures, social distancing and face masks, and realistic future advances, this paper focuses on the consequences of taking no public health action; the role of natural changes such as weather; the adverse public health consequences of lockdowns; testing for surveillance and research purposes; testing to identify cases and contacts, including the role of antibody tests; the public health value of treatments; mobilising people who have recovered; population (a synonym for herd) immunity through vaccination and through natural infection; involving the entire population; and the need for public debate. until there is a vaccine, population immunity is going to occur only from infection. allowing infection in those at very low risk while making it safer for them and wider society needs consideration but is currently taboo. about - % population immunity is sufficient to suppress an infection with a reproduction number of about or slightly more. importantly, in children and young people covid- is currently rarely fatal, roughly comparable with influenza. the balance between the damage caused by covid- and that caused by lockdowns needs quantifying. public debate, including on population immunity, informed by epidemiological data, is now urgent. in public health, as in chess, planning well-ahead is essential. many leaders, however, are hesitant about articulating long-term plans for tackling the covid- pandemic. discussing future options might distract from the stay-at-home and social distancing messages. leaders are focused on immediate tasks including 'the peak' of hospitalisations and deaths, but reaching it will mean negotiating treacherous downhill terrain . ( ) the covid- pandemic has placed us in zugwang-a position in chess where every move is disadvantageous where we must examine every plan, however unpalatable. curative treatments and vaccines may be long-delayed and lockdowns harm the public's physical and mental health and not just the economy. mass testing will not be feasible globally especially in many low and middle-income countries, as it is in the well organised, advanced economies like the us and germany. we need to think beyond these interventions. an overview of public health options is summarised in table , constructed around the classic public health triad of primary (stop it occurring), secondary (pick it up early) and tertiary prevention (minimise the consequences) and interventions on the viral agent, host/population and environment. ( ) this classification is normally applied to individuals but in this paper i also use it for populations. this analysis fits with the who strategy update published on april ( ) and subsequent updates on its website, and an outline of options by bedford et al. ( ) i focus on core public health issues considering their relevance to population immunity, commonly called herd immunity, and used here as a better synonym. this is the protection from a contagious disease that the community enjoys because a high proportion of people are immune, thereby impeding transmission of infection from person to person. it is normally invoked through vaccination but also occurs naturally. ( , ) many important matters are in the table that are not fully discussed in this paper e.g. that research on the transmission, infective dose and changing genetics, and especially virulence of the virus (agent), is essential (column , table ). pinpointing the causes of the high risk in older populations, males, and people with cardiovascular disorders and type- diabetes is paramount. i assume that interventions targeted on the host/population including hygiene measures, avoiding handshaking and social distancing will be prolonged, that lockdowns will be imposed perhaps intermittently and with variable intensity, and that the role of face masks and temperature checks in public life will become clearer (column , table ). ( , ) public health surveillance systems and epidemiological research must be strengthened with more accurate data on incidence, prevalence, and death rates examined by both demographic variables including age, sex, socio-economic status and ethnicity/race and clinical risk factors (column , table ). environmental changes, permitting behavioural changes including social distancing and hygiene, especially in overcrowded housing and working settings, will be needed (column three, table ) as will effective, comprehensive healthcare together with financial aid for industries (column , table ). early and even ongoing trivialisation of covid- as 'just like flu' was incorrect for it is somewhat less severe in children but much more severe in older people (table ) . ( ) the world health organisation (who) estimates that about % of those diagnosed become seriously ill, % critically , and % die.( ) (as the number of people infected is usually unknown the infection fatality rate is variably estimated at between . - . %.) if - % of the world's population was infected without interventions there could be about - billion people infected with covid- , one billion seriously sick and up to million dead prematurely. there will be indirect consequences from the infection, lockdown measures and economic damage e.g. starvation, homelessness, poverty and mental health and physical morbidity and death. the collateral damage will be especially high in low and middle income countries and in children. ( ) that happened with the spanish flu epidemic in / .( ) the covid- pandemic arises during one of the most prosperous periods in human history permitting a more vigourous response than in . allowing the pandemic to unfold uncontrolled would rapidly produce population immunity, but this is not a palatable public health response, hence is not in table . pandemics can fizzle out. we hope this will happen with covid- . this is not a public health intervention and not in table . in the spanish flu epidemic there was a respite before the virus returned more virulently .( ) summers might bring respite even if lockdowns are relaxed but the virus seems to survive and be contagious in most climates. infection in summer may be less common and less severe than in winter because other respiratory infections are less common and being outdoors presents lower risk of acquiring infection than indoors. in very hot climates, however, people go indoors to escape the heat. lockdowns are important in primary, secondary and tertiary prevention (table , column ). most nations are applying strict lockdowns for - weeks, but as the who emphasises, this merely provides time to reduce the reproduction rate of infection (r) from about three to less than one.( ) the lockdown in wuhan, china was severe and strict from january- april, about weeks. however, life there is not normal even now and the infection has recurred. hubei province, where wuhan is, has about million people in china i.e. less than % of the population. the province, unlike countries, had access to the resources of the nation to survive. some economies cannot sustain even - week lockdowns and they are being lifted or breaking down within weeks e.g. after three weeks in ghana, and some places are resisting them e.g. brazil.( ) prolonged lockdowns may cause more morbidity and mortality than covid- , especially in the poorest countries, where the populations are relatively young on average and at little risk of death. we must evaluate the health consequences of lockdowns, assessing the benefits and costs. ( ) lockdowns are likely to become variable and local, depending on circumstances. mixing amongst local populations is already occurring and widespread international travel is returning. a uk-based strategy has suggested easing lockdowns when widespread testing is in place and when the number of daily deaths is below ( , deaths annually), and relaxing most measures when deaths are fewer than ( , deaths annually). ( ) the uk government seems to be following this approach in england, with more cautious approaches in scotland, wales and northern ireland. during lockdowns population immunity is being acquired slowly, and those at highest risk of severe morbidity and death are being shielded. population immunity will be accelerated as lockdowns are eased. testing is vital for both primary, secondary and tertiary prevention, and helps identify places where the disease has not yet occurred (table , column ). who has emphasised testing as key until a vaccine or a cure are discovered( ) but the reasoning is seldom explicit to the public. testing in selected populations is essential for public health surveillance and medical research to establish the incidence, prevalence and outcomes of the disease (table , column ). ( , ) such data help adjust our plans through feedback including indicating the proportion of the population that has acquired the infection and is potentially immune. the benefit of detecting the virus or the viral antigen in suspected cases is accurate diagnosis for clinical management (including protection of frontline staff) and to permit isolation/quarantine of proven cases. tracing of contacts becomes possible so they can be isolated to minimise spread. this is better than asking everyone with respiratory symptoms to isolate without doing tests but it requires extensive public health infrastructures (in addition to apps) and access to laboratories and testing kits (column , table ). to work, both testing and feedback of results must be prompt. testing helps control the acquisition of population immunity. testing for virus and antigen is also useful to check whether people recovering from covid- can return to normal without infecting others or harming themselves by premature activity (tertiary prevention) (column , table ). people who have recovered will need to be careful as their immunity may be partial and some may continue to shed the virus.( ) some recovered people, especially in essential services who have already returned to work, may be shedding virus but whether these people are contagious needs research. immunity to respiratory viruses is complex but cellular responses by macrophages and lymphocytes, including t-cells, are critical.( ) antibody, whether igm or igg, is a marker of potential immunity but its absence does not necessarily imply lack of immunity. people who have recovered from proven covid- must be partially immune. ( ) adults with mild or even asymptomatic illnesses may not mount a strong antibody response but like children probably have a strong, innate defence system. ( , ) we need an accurate antibody test to identify, retrospectively, people who have been infected and several are available. when the population prevalence is about % as is the case in many countries, even at % sensitivity and specificity only about % of positive tests are correct (predictive power of a positive test). ( ) higher accuracy could be achieved by using more than one kind of test. people who have self-isolated because of typical covid- symptoms and have antibody have probably had covid- and are partially immune. some false positives and false negatives are still inevitable. ( , ) nonetheless, antibody tests are invaluable for measuring the prevalence of population immunity (table , column ) . surprisingly, the accuracy of a test required to measure prevalence is usually different from the accuracy required for clinical practice. ( ) mobilising people who have recovered we need to normalise recovered people, especially those delivering essential services. the concept of immunity passports has been discussed. immunity passport implies a guarantee that cannot be given but a certificate indicating that a person has had the infection, has recovered clinically and is likely to be partially or wholly immune is more accurate. ( ) the number of eligible people globally could soon be in the hundreds of millions so the clinical, ethical, legal, and practical issues arising need urgent consideration. ( ) ( ) ( ) i have called for public debate including a citizen's jury. ( ) the ideal treatment would be preventative i.e. it would stop the infection occurring (column , table ). such treatment would, however, need to be extremely safe, especially in young people without underlying disorders where covid- is rarely fatal. (table )( ) it would probably be unaffordable for low-and middle-income countries. more likely, treatments may attenuate the illness, reducing the duration and fatality of the infection. ( , ) they could be valuable in public health in reducing the transmission of disease, especially to healthcare workers (column , table ). this will slightly slow the acquisition of population immunity. people with comorbidities, who are usually in the older age groups, are most severely affected by covid- , and especially if they have cardiovascular disorders, type diabetes, hypertension, and chronic respiratory disorders. ( , ) clearly, public health interventions should promote control of risk factors that lead to these diseases e.g. smoking, physical inactivity, high levels of alcohol consumption, high levels of salt and exposure to air pollution (column , table ). people in these groups could minimise their risk of exposure to covid- , await effective vaccination and benefit indirectly as population immunity through natural infection increases (column , table ). ( , ) involving the entire population especially those most vulnerable as the who has emphasised the strategy for controlling covid- needs to be global, and reach out to everyone. (column , table ) the who has emphasised the needs of populations in crowded circumstances, including asylum seekers, refugees and migrants, where the infection can spread readily. ( , ) regulations and laws making it illegal or difficult to house, employ or provide health and other services to vulnerable people (e.g. undocumented migrants, who cannot access public funds), need to be reviewed, especially as international travel is problematic. ( ) the pandemic hits minorities and migrants hard, given their greater overcrowding in homes and workplaces, relative poverty, the difficulties of understanding and acting upon social distancing guidelines, and the propensity to cardiovascular diseases and type diabetes. ( ) ( ) ( ) large numbers of such populations are being infected but being relatively young, comparatively fewer will die from covid- , thereby contributing disproportionately to population immunity. vaccination is the acceptable way of gaining population immunity, and our main hope for controlling the pandemic (columns and , table ).( , , ) numerous trials to develop a vaccine are underway and the who has set up a vaccine task force.( ) we cannot, unfortunately, pin all hopes on vaccines as they may only work for a short time especially if the virus evolves new strains. a vaccine that is effective, proven to be safe, manufacturable in billions of doses and available globally is unlikely this year, and may take years, even decades. proven safety is essential especially in children or young people.( ) serious illnesses or deaths in young people following immunisation, whether coincidental or causal, could impede vaccination. in people over -years of age, or the immunosuppressed, where the vaccine is needed most, a strong immune response is unlikely. efficacy of vaccines needs to be demonstrated in older groups and in those with underlying disorders. the technical phrase is herd immunity, with connotations of animals, rather than humans. herd immunity provokes hostility and controversy as it is usually interpreted as allowing the pandemic to unfold without interventions. the concept needs revisiting. if safe and effective vaccines and life-saving preventative and therapeutic medications are not found, lengthy lockdowns prove impossible, and the pandemic does not disappear spontaneously, population immunity is the only, longterm solution (column , table ). everyone infected and achieving any degree of immunity contributes to population immunity, ( ) and this is likely to be through a combination of cellular and antibodybased (humoral) responses. the duration of such immunity is unknown although it is reasonable to assume it will last this season with some long-term benefits given exposure to the same or similar strains of the virus. through social distancing and lockdown measures most societies have brought the reproduction number from about three ( ) to about one or less. the proportion of the population required to be immune to control an infection is called the herd (population) immunity threshold. it is difficult to calculate this number exactly in real world circumstances. to control an infection with an r of about and even somewhat higher we need about % of the population to have immunity (unlike measles where over % is needed).( , ) currently, the prevalence of covid- infection is variably estimated from - % according to locality and work settings. however, if covid- becomes endemic, the proportion of the population with immunity will rise fast, especially where lockdowns have been lifted .( ) this immunity will be helpful, though not fully protective, as new strains of covid- will probably emerge, so people will be re-infected but probably less severely so, as is the case for influenza. opening up the economy, schools, colleges and social life is accepting that many people will become infected even with test, track and isolate strategies. most young people will probably acquire the infection, often without a diagnosis as they will be asymptomatic or mildly affected. given this, we need to minimise the already low risks of adverse effects in young people (table ) , especially by identifying the reasons why a few become seriously ill. ( , ) hygiene and some social distancing measures will continue to be required in homes as children and young people return to nurseries/school/colleges. ( , , ) some young people with immunity related disorders could be advised not to return to school or university presently, while awaiting the rise of population immunity in their classmates, which will protect them indirectly. young people present risks to transmitting covid- to people in their household, especially parents and grandparents who have underlying disorders or are in the oldest age groups. home school may be needed for children in these exceptional circumstances. teachers and others in close contact with children and young people, especially those in older age groups and with chronic disorders, need shielding and/or personal protection equipment. we need excellent facilities for diagnosis, isolation, quarantine, and treatment for these young people and their contacts as they return to normal life. the public will need to be informed frankly about the risks by comparing those of covid- with infections they are familiar with e.g. influenza (table ) . ( ) the idea of covid- 'parties' by young people has been met with shock. intermingling is inevitable as workplaces, schools, colleges and universities are reopened. young people will make decisions that are logical for them given their risks and life circumstances. could we consider allowing young people without underlying disorders to get covid- naturally while shielding those most at risk through continued social distancing and isolation? ( , , ) young people might prefer this route rather than remaining in lockdown or acquiring the infection in riskier circumstances e.g. while travelling abroad. such people could be given advice and lightly monitored to minimise adverse effects. this is not unprecedented. chickenpox parties were occurring even in the s even though such infections posed risk to pregnant women and the ethics have been considered. ( ) the acquisition of covid- naturally by the young and healthy is, arguably, the safest way towards the goal of about % population immunity while protecting those most at risk and maximising benefits for society, whether in terms of the economy or achieving the full potential of future generations. ( , ) this question poses ethical, legal, logistical and clinical challenges similar to those arising in the proposal to test covid- vaccines in healthy volunteers.( ) allowing the covid- pandemic to run its course uncontrolled must not be permitted. none of the responses of countries internationally are optimal as partly reflected in their variability.( , ) covid- has placed us in zugzwang so we need precise and detailed plans and well-calculated series of moves that minimise the harms, tailored for each country and region according to their context and resources. the pandemic needs to be prevented from returning year-on-year, potentially more severely, especially in young people and children, and mandating repeated lockdowns.( ) we urgently need to consider all reasonable public health actions and plans (table ) . hope in natural forces, effective and safe vaccines and curative treatments is important but, given uncertainty, we need to consider other, admittedly difficult, paths. adults should now reflect on and debate, together with their elected policymakers and scientific advisers, the balance of risks they accept for themselves, versus the risks imposed to wider society, and thus directly inform potential strategies. covid- is having a major impact on children and their voice needs to be heard. ( ) ageism must be avoided whether through shielding or workplace policies that might inadvertently cause harm. everyone has the right to balance risks and benefits in relation to their own quality of life. this pandemic is complex while the messages being given to the public are overly simplistic. we need global and national leadership, imagination, courage and honest public discussion to shape and influence our future.( , ) table the levels of prevention in relation to the causal triad of virus (agent), the human host and the environment (physical and social) and the control of covid- , applied at both individual and population levels (or both) covid- -a framework for decision making. edinburgh: the scottish government concepts of epidemiology : integrating the ideas, theories, principles and methods of epidemiology covid- : towards controlling of a pandemic individual variation in susceptibility or exposure to sars-cov- lowers the herd immunity threshold herd immunity": a rough guide case isolation, contact tracing, and physical distancing are pillars of covid- pandemic control, not optional choices. the lancet infectious diseases physical distancing, face masks, and eye protection to prevent person-to-person transmission of sars-cov- and covid- : a systematic review and meta-analysis. the lancet children's mortality from covid- compared with all-deaths and other relevant causes of death: epidemiological information for decisionmaking by parents, teachers, clinicians and policymakers early estimates of the indirect effects of the covid- pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study. the lancet global health on the centenary of the spanish flu: being prepared for the next pandemic a sustainable exit strategy: managing uncertainty, minimising harm test, test, test for covid- antibodies: the importance of sensitivity, specificity and predictive powers. public health rapid roll out of sars-cov- antibody testing-a concern positive rt-pcr test results in patients recovered from covid- immunity to respiratory viruses the immune system of children: the key to understanding sars-cov- susceptibility? the lancet child & adolescent health patients who have recovered from covid- : issuing certificates and offering voluntary registration covid- immunity passports and vaccination certificates: scientific, equitable, and legal challenges. the lancet chile plans controversial covid- certificates. the lancet remdesivir in adults with severe covid- : a randomised, double-blind, placebo-controlled, multicentre trial. the lancet effect of dexamethasone in hospitalized patients with covid- : preliminary report covid- ) and cardiovascular disease global, regional, and national estimates of the population at increased risk of severe covid- due to underlying health conditions in : a modelling study. the lancet global health evaluation of "stratify and shield" as a policy option for ending the covid- lockdown in the uk rohingya refugees at high risk of covid- in bangladesh. the lancet global health covid- : immense necessity and challenges in meeting the needs of minorities, especially asylum seekers and undocumented migrants is ethnicity linked to incidence or outcomes of covid- ? covid- and african americans sharpening the global focus on ethnicity and race in the time of covid- . the lancet the dual epidemics of covid- and influenza: vaccine acceptance, coverage, and mandates safety, tolerability, and immunogenicity of a recombinant adenovirus type- vectored covid- vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial the reproductive number of covid- is higher compared to sars coronavirus hyperinflammatory shock in children during covid- pandemic. the lancet covid- in children and adolescents in europe: a multinational, multicentre cohort study. the lancet child & adolescent health how to hold an ethical pox party human challenge studies to accelerate coronavirus vaccine licensure. the journal of infectious diseases singapore: university of singapore national what's the way out? potential exit strategies from the covid- lockdown a future for the world's children? a who unicef commission. the lancet professor martin mckee posed the questions on april that initiated this paper on april . i thank him for his feedback at that time. i am grateful to professional colleagues will tapsfield, anand bhopal, sunil bhopal jay bagaria, viola priesmann, jason yap, sarah dalglish, david mccoy, and laurence gruer george davey smith, liam smeeth , joan barry, neil french, john teare, paul roderick, and paolo vineis for detailed critical scrutiny of earlier dtafts from a medical and public health perspective. roma bhopal, sanjoy das, mark wilson, and ulrike wilson provided viewpoints from the perspective of members of the general public. roma bhopal also helped find age-specific data and help with proofreading and editing. people acknowledged are not responsible for any of the viewpoints expressed here (and may not agree with me). i have no conflicts of interest to declare. there was no external funding for this work. deaths with confirmed or presumed covid- , coded to icd- code u . . influenza death counts include deaths with pneumonia or covid- also listed as a cause of death. population is based on postcensal estimates from the u.s. census bureau ( ) ☒ the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐the authors declare the following financial interests/personal relationships which may be considered as potential competing interests: key: cord- -x mqxif authors: tatarinova, tatiana v.; tabikhanova, ludmila e.; eslami, gilda; bai, haihua; orlov, yuriy l. title: genetics research at the "centenary of human population genetics" conference and sbb- date: - - journal: bmc genet doi: . /s - - - sha: doc_id: cord_uid: x mqxif nan structure \ systems biology) (https://bgrssb.icgbio.ru/ ) multiconference with genetics sessions [ , , ] . the sbb- school was held as a broad-scope independent meeting, genetics in topics with the human genomics and bioinformatics areas. the special issue on bioinformatics is accompanied by other bmc journal issues in the genomics, bioinformatics, and medical genetics areas at bmc bioinformatics, bmc genomics, bmc medical genomics, and bmc medical genetics, as well as in bmc microbiology. we continued the bmc genetics special issues in [ , , ] . we believe such events and public discussion at the platforms of international publishers will bring the attention of the journal readers to actual genomics challenges. we open up this special issue by the human population genetics study in africa by the article by sandra walsh and colleagues [ ] (this issue). african populations are genetically more diverse than any other human population, holding the highest amount of genetic variation, low linkage disequilibrium, and deep population structure. in the process of adaptation of humans to their environment, positive or adaptive selection has played a main role. positive selection has been understudied in african populations and less presented in such databases as genome project [ ] . the authors used about hundred of available whole-genome sequences from five ethiopian populations to investigate the modes and targets of positive selection. walsh and colleagues found population-specific and shared signals of selection, with folate metabolism and the related ultraviolet response and skin pigmentation standing out as a shared pathway, possibly as a response to the high levels of ultraviolet irradiation, and in addition strong signals in genes such as ifna, mrc , immunoglobulins and t-cell receptors which contribute to defend against pathogens. maxat zhabagin et al. [ ] (this issue) present population genetics study in continental asia. the authors analyzed the medieval mongolian roots of paternal lineages from kazakhstan. the majority of the kazakhs from south kazakhstan belong to the twelve clans of the senior zhuz. according to traditional genealogy, nine of these clans have a common ancestor and constitute the uissun tribe [ ] . the authors have genotyped samples of south kazakhs by set of y-chromosomal snps. the y-chromosomal variation in kazakh clans indicates their common origin in medieval times, in agreement with the traditional genealogy [ ] . zhabagin and coauthors show that the y-chromosomal lineages of south kazakhstan were brought by the migration of the population related to the medieval niru'un mongols. work by vladimir babenko and colleagues [ ] (this issue) analyze continental populations for variability in optical disk size morphology. gfi (growth factor independent transcription repressor ) is a development gene which is likely to affect optic disk area by altering the expression of the associated genes via long-range interactions. role of gene regulatory regions in the human genome were discussed in [ ] as part of special postconference supplement issues at biomed central distribution of haplotypes in the putative enhancer region has been assessed using the data on four continental super groups from the genomes project. the major haplotype appears to be involved in silencing gfi repressor gene expression, which might be the cause of increased optic disk area characteristic of the east asian populations. ramjet das and priyanka upadhyai [ ] analyzed the kumhar and kurcha populations from the india. the authors investigated the genetic origin and population history of the kumhars, a group of people who inhabit large parts of northern india using the geographic population structure method developed earlier [ ] . das and upadhyai compared previously published kumhar snp genotype data sampled from uttar pradesh in north india to various modern day and ancient populations. the analysis show high genomic proximity to the kurchas, a small and relatively little-known population found far away in kerala, south india. the findings illuminate the genomic history of two indian populations, allowing a glimpse into one or few of numerous of human migrations that likely occurred across the indian subcontinent [ ] . rosa tiis and co-authors [ ] (this issue) studied polymorphic variants of the nat (n-acetyltransferase ) gene in native populations of siberia. nat plays a crucial role in the metabolism of a wide range of xenobiotics, including many drugs, carcinogens, and other chemicals in the human environment [ ] . this work presents for the first time data on the frequency of two variants of nat gene, which significantly affect the rate of xenobiotics acetylation, among the representatives of indigenous populations of forest and tundra nenets in northern siberia. genetic predispositions to diabetes and related diseases among native mongolian populations were studied by the authors' group earlier in [ , ] . the work by mikhail ponomarenko and colleagues [ ] (this issue) covers fundamental evolution problems of natural selection by male reproductive potential. the concept of reproductive potential denotes the most vital indicator of chances to produce and sustain a healthy descendant. the authors continued study on singlenucleotide polymorphisms (snp) in tata-binding protein binding sites in human gene promoters [ , ] . the authors found in silico new candidate snp markers of male reproductive potential. the other works consider genetics application in model organisms. these articles discuss genetics application in drosophila, highlighted, in turn, at sbb' school in novosibirsk. anna ogienko et al. [ ] (this issue) analyzed drosophila lines for gal gene. the authors provide a miniatlas of the spatial activity of gal drivers that are widely used for the expression of uas genes in the drosophila [ , ] . mikhail shaposhnikov and co-authors [ ] (this issue) consider problems of aging and affecting life span on fruit flies. beta-amyloid peptide (aβ) is the key protein in the pathogenesis of alzheimer's disease, the most common age-related neurodegenerative disorder in humans. the authors used the drosophila model [ ] to study mechanisms underlying a dual role for aβ peptides. the work by natalia blazhko et al. [ ] concludes this issue by analysis of virulence properties for bovine leukemia virus. this study describes the biodiversity and properties of this virus in western siberia. the paper explores the effect of different genotypes of the env gene of the cattle leukemia virus on hematological parameters of infected animals. the authors note that monitoring the origin of new virus mutations is of great importance for veterinary and animal husbandry, as every new strain may have unique features of interaction with the host organism. the problems of hazards control in food safety related to infectious diseases became important due to the sars-cov- pandemic [ ] . genetics studies on model organisms have new value in relation to the infectious disease resistance, adaptations of human populations to environment, and natural polymorphism. we aim to support international exchanges and education in the form of international conferences and schools for young scientists on bioinformatics, genetics and systems biology [ ] (https://peerj.com/collections/ -bgrssb- /). we invite our readers worldwide to attend the systems biology meetings in russia -digital medicine forum and mgngs- (medical genetics -next-generation sequencing) event postponed to (http://ngs.med-gen.ru/mgngs /). this article has been published as part of bmc genetics volume supplement , : selected topics in "systems biology and bioinformatics" - : genetics. the full contents of the supplement are available online at https://bmcgenet.biomedcentral.com/articles/supplements/volume- supplement- . authors' contributions tt, and yo are guest editors of the special post-conference issues and program committee members of sbb- school. lt, ge, hb are the invited editors and the committee members of the conferences. all the authors read, revised, and approved the final manuscript. publication of this article was not covered by sponsorship. the authors declare that they have no competing interests. the papers presented at th young scientists school "systems biology and bioinformatics" (sbb' ): introductory note computational genomics at bgrs\sb- : introductory note editorial -bioinformatics development at the bgrs\sb conference series: th anniversary editorial: bioinformatics of genome regulation and systems biology computational models in genetics at bgrs\sb- : introductory note genetics at belyaev conference - : introductory note genomics research at bioinformatics of genome regulation and structure\ systems biology (bgrs\sb) conferences in novosibirsk computer genomics research at the bioinformatics conference series in novosibirsk positive selection in admixed populations from ethiopia the african genome variation project shapes medical genetics in africa the medieval mongolian roots of paternal lineages from south kazakhstan molecular genetic analysis of population structure of the great zhuz kazakh tribal union based on y-chromosome polymorphism whole-sequence analysis indicates that the y chromosome c *-star cluster traces back to ordinary mongols, rather than genghis khan analyzing a putative enhancer of optic disk morphology genomic landscape of cpg rich elements in human genome the story of the lost twins: decoding the genetic identities of the kumhar and kurcha populations from the indian subcontinent application of geographic population structure (gps) algorithm for biogeographical analyses of populations with complex ancestries: a case study of south asians from genomes project between lake baikal and the baltic sea: genomic history of the gateway to europe studying polymorphic variants of the nat gene (nat * and nat * ) in nenets populations of northern siberia population genetic diversity of the nat gene supports a role of acetylation in human adaptation to farming in central asia association analysis of genetic variants with type diabetes in a mongolian population in china genetic polymorphisms and related risk factors of ischemic stroke in a mongolian population in china disruptive natural selection by male reproductive potential prevents underexpression of protein-coding genes on the human y chromosome as a self-domestication syndrome candidate snp markers of reproductive potential are predicted by a significant change in the affinity of tata-binding protein for human gene promoters candidate snp markers of aggressivenessrelated complications and comorbidities of genetic diseases are predicted by a significant change in the affinity of tata-binding protein for human gene promoters molecular and cytological analysis of widely-used gal driver lines for drosophila neurobiology new slbo-gal driver lines for the analysis of border cell migration during drosophila oogenesis a toolset to study functions of cytosolic non-specific dipeptidase (cndp ) using drosophila as a model organism moskalev aa amyloid-β peptides slightly affect lifespan or antimicrobial peptide gene expression in drosophila melanogaster the influence of pro-longevity gene gclc overexpression on the agedependent changes in drosophila transcriptome and biological functions genotypes diversity of env gene of bovine leukemia virus in western siberia possibility of faecal-oral transmission of novel coronavirus (sars-cov- ) via consumption of contaminated foods of animal origin: a hypothesis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - xgk g authors: edwards, todd l.; breeyear, joseph; piekos, jacqueline a.; velez edwards, digna r. title: equity in health: consideration of race and ethnicity in precision medicine date: - - journal: trends genet doi: . /j.tig. . . sha: doc_id: cord_uid: xgk g the causes for disparities in implementation of precision medicine are complex, due in part to differences in clinical care and a lack of engagement and recruitment of under-represented populations in studies. new tools and large genetic cohorts can change these circumstances and build access to personalized medicine for disadvantaged populations. the causes for disparities in implementation of precision medicine are complex, due in part to differences in clinical care and a lack of engagement and recruitment of under-represented populations in studies. new tools and large genetic cohorts can change these circumstances and build access to personalized medicine for disadvantaged populations. in 'more than half of the nation's children are expected to be part of a minority race or ethnic group,' according to us census bureau [ ] . evidence of this changing demographic is seen in the genetic composition of the us population, where multiple studies have shown an increase in ancestral variation since the mid- s when social and legislative barriers to inter-racial marriage were struck down [ ] . further support that this is a recent change are us census data showing that, in , % of the us population aged - years identified as being more than one racial/ethnic group compared to only % of those aged - years [ , ] . unfortunately, there is currently limited representation of minorities and disadvantaged populations in scientific research, despite increasing diversity in the us. this situation increases the risk of perpetuating and exacerbating health disparities. increased knowledge of disease risks and patterns across diverse populations is important to mitigate impacts of disease, and without this knowledge the benefits of research will be unequally realized. health disparities are present across a wide variety of diseases and health conditions. differences in socioeconomic status, access to care, stress, lifestyle, and genetics have been proposed for these disparities. genetic factors likely contribute to many disease disparities, but limited progress has been made in understanding genetic determinants of disparity and their interactions with environmental, behavioral, and social determinants of health. most largescale genetic studies (n %) have focused on european ancestry populations [ ] , despite an acknowledged need to increase the intensity of research in minority groups [ ] . this is problematic because genetic predictors of disease in european ancestry populations do not consistently maintain predictive power in other populations and use of poorly calibrated models could exacerbate disparities [ ] . health inequity is a long-standing issue in the us healthcare system. social determinants of health, including poverty, lack of access to quality education, lack of access to quality healthcare, unfavorable work and neighborhood conditions, and the clustering of disadvantaged groups of people, are often cited as leading causes of these disparities [ ] . additionally, studies indicate that although minority and disadvantaged populations are most directly impacted by health disparities, rural populations, regardless of age, race, sex, or sexual orientation are also affected [ ] . those who are economically disadvantaged, whether due to living in a rural area or being a member of an economically disadvantaged community face several common factors that contribute to health disparities. these include gaining entry to the healthcare system, accessing a location where services are available, and maintaining services with a trusted provider. chronic disease treatment requires multiple clinical encounters, access to medication, and updating treatment plans to provide adequate care, making unequal access an important cause of disparities. uninsured people face barriers to entry for healthcare services, and this group is more likely to die prematurely, have illnesses, and be diagnosed later than insured people [ ] . a review of studies additionally demonstrated that between % and % of patients reported access to care was inhibited by transportation [ ] . people with consistent access to care with a primary care physician have lower mortality from all causes [ ] . a holistic approach to the precise application of medical resources to reduce disease burdens would address these issues as well as underlying biological differences between people. in addition to environmental conditions such as nutrition, pathogens, climate, economic, social, and cultural factors that influence health disparities, evolutionary adaptations to historical environmental stresses can also contribute. examples of this include high rates of diabetes in the native american pima tribe after exposure to a western diet [ ] , and adaptation at the apol gene locus to resist the trypanosomiasis parasite that causes african sleeping sickness, but also leads to kidney disease [ ] . the alleles that contribute to these disparities were swept to high frequency by natural selection but also confer increased risk of disease, and so whether they are in general beneficial or deleterious depends on the context the population that carries them lives in. other traits with geographic variation in humans, such as skin pigmentation, lactase persistence, dietary adaptations, and altitude tolerance have also been influenced by natural selection. the observation of a geographic disparity does not always imply underlying differences in genetic risk factors between populations, which is well discussed by rosenberg et al. [ ] . when genetic differences are accurately detected, they may reflect biological factors that would be ideal targets for precision medicine development. the sars-cov- pandemic is an example of current health disparities and health inequity. the centers for disease control and prevention reported that . % of a representative subset of those who tested positive for coronavirus disease (covid- ), as of march , had one or more comorbidities [ ] . furthermore, these comorbidities that are at higher rates among minorities, including hypertension, obesity, diabetes mellitus, and cardiovascular disease, have been identified as potential biological vulnerabilities for more severe covid- outcomes. these findings are evident in the mortality rate for covid- in chicago and new york city. i the age-adjusted covid- mortality rate is greatest among african-american/black individuals ( . per ) compared with latino ( . per ) and european ancestry/white ( . per ) individuals. i in new york city, the ageadjusted covid- mortality rates are similar among latino ( . per ) and african-american ( . per ) individuals, while both are higher than among european ancestry ( . per ) residents. ii the causes for these differences are not yet fully understood, but the documented inequity in healthcare access has both contributed to the extent and severity of the ongoing disparity in the pandemic in the us. the development of precision medicine approaches to improve accuracy of diagnoses, understand biological and environmental elements of disease risk, and improve safety and efficacy of treatments has been relatively slow within minority and disadvantaged populations. the pursuit of personalized medicine is a high priority at large academic medical research centers where incorporating genetic information into clinical records has become more common. however, these approaches are often inaccessible to economically disadvantaged populations and those who live in more rural areas. precision medicine has been successful historically. early examples of precision medicine come from the diagnosis and characterization of inborn errors of metabolism such as phenylketonuria [ ] . these disorders are individually rare, but collectively common and can often be mitigated or cured by restoring homeostasis to the disrupted metabolic pathway, in some cases through genotyping. more recent examples have improved drug safety by characterizing dosing responses to drug treatments such as with the anticoagulant coumadin (warfarin), which avoids drug titration protocols. there is use of different treatment strategies for hypertension in african compared with european ancestry populations, where antirenin drugs are more effective in european ancestry, while volume-lowering treatments with diuretics and calcium channel blockers show better outcomes in african-ancestry patients. other examples include cancer diagnoses such as breast cancer (brca) and pregnancy and prenatal screenings using rh testing and fetal genetic testing [ , ] . the reasons minorities and economically disadvantaged populations have had limited access to personalized medicine are complex and directly tied to the causes of health disparities. these causes are described earlier, and also include distrust of researchers combined with a lack of consistent long-term community engagement and other strategies to increase diversity in recruitment from under-represented populations for clinical studies. as genome-wide association study platforms were developed to accommodate diverse populations, collections of biological samples linked to electronic health records as well as health and lifestyle surveys also started to become more common. early biobanks were often assembled from clinical populations with sampling biases relative to cohort studies, but were also able to recruit relatively large numbers of minority participants. national and university-level biobank programs have since been established in the uk, japan, finland, iceland, estonia, china, and the us, and offer researchers unprecedented opportunities to ask research questions and study genetic causes for health disparities in diverse samples of participants. additionally, research resources developed by direct-to-consumer genetic testing companies include substantial numbers of minority participants with diverse ancestries. recently, the chief executive officer for the company andme issued a statement that acknowledged the genotyping platform used by the company should be improved to better evaluate non-european genetic backgrounds, with ancestry.com making a similar statement, shortly afterward. health disparities exist in the us within the context of historical and current racial discrimination along with social and economic inequity. comprehensively addressing these disparities requires changes in systems beyond the fields of medicine and medical research. however, researchers have a critical role in identifying novel treatments and strategies to mitigate disparities. the continued development of technology, population resources, and sustained engagement with minority communities are critical to this endeavor. the national institutes of health has made improving the health of minorities and reducing health disparities part of their trends in genetics primary mission, with targeted research funding and development of research tools focused on community engagement. recognition of the additional burdens on health of minorities, the weaknesses of existing research resources, research opportunities, and the challenges of finding substantive solutions to these issues, is an end to the beginning of the work to provide equitable access to healthcare resources. projections of the size and composition of the us population: to . in population estimates and projections. current population reports temporal changes in genetic admixture are linked to heterozygosity and health diagnoses in humans the most common age among whites in us is -more than double that of racial and ethnic minorities clinical use of current polygenic risk scores may exacerbate health disparities genomics is failing on diversity evaluating strategies for reducing health disparities by addressing the social determinants of health insurance coverage, medical care use, and short-term health changes following an unintentional injury or the onset of a chronic condition traveling towards disease: transportation barriers to health care access australian lesbian and bisexual women's health and social experiences of living with hepatitis c. health care women int high-risk populations: the pimas of arizona and mexico association of trypanolytic apol variants with kidney disease in african americans interpreting polygenic scores, polygenic adaptation, and human phenotypic differences hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease -covid-net, states a simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants genetic testing strategies in the newborn population-based genetic testing for women's cancer prevention trends in genetics, month , vol. xx, no. xx key: cord- -f yt a authors: parmet, wendy e.; robbins, anthony title: public health literacy for lawyers date: - - journal: j law med ethics doi: . /j. - x. .tb .x sha: doc_id: cord_uid: f yt a nan lic health advocacy institute, with support from the centers for disease control and prevention, assembled experts froni legal education, public health practice and education, the judiciary, foundations, and the publishing industry to consider what changes would have to occur in legal education so that law graduates would be "literate" in public health and how those changes could come about.b in this article we build upon the intense discussions of the conference participants. we make the case for introducing public health into the core law school curriculum and suggest the content that would be needed to achieve public health literacy among law students. we also argue that public health's focus on populations, aided by the tools of epidemiology, provides a valuable prism for understanding the relationship of individuals and groups and the ways that laws can and ought to affect them. we conclude by urging the development of a body of scholarship and analysis that brings the insights of public health to bear on legal questions. law schools might introduce public health to their students in several ways. most comprehensively, law students can enroll in a j.d./m.p.h. program, and receive the training given public health graduate students for a masters degree in public health. while such programs are increasingly common, they are obviously intended for students already committed to careers at the intersection of law and public health. thus jd/mph programs do not reach the vast majority of law students. a larger number of law students can i x exposed to public health in upper level electives that focus on public health law or a particular topic closely related to public health, such as aids law or food and clnig lawn undoubtedly, the content and the extent of exposure to public health principles and methocls will vary widely depending on the particular topic of the class. through these courses, law schools can provide :i limited number of students with in-depth exposure to one or more public health problems and the legal tools and doctrines most relevant to those topics. law faculty and public health professionals at a workshop' dedicated to developing a curriculum on bioterrorisin concluded, for example, that a hasic understanding of public health powers woulcl be an essential part of any course on bioterrorism. most law students, however, will never get ;i mph or take a public health oriented elective in law school. if they are to be introduced to public health in the course of their legal training, it will have to be within existing, core law school courses, the courses that are generrilly required of first year students or taken almost universally by upper level students. at the public health literacy conference, the lawyers present identified several such courses-tom, constitutional law, environmental law, and administrative law-as prime candickites for the inclusion of public health. attendees also recognized that the integration of public health into such courses would be d#icult to achieve given legal education's traditional reluctance to embrace significant reforms. nevertheless, attentlees agreed that it was important to pursue the effort. what public health knowledge or set of skills should all law students acquire? if these could be identified, educators from law and public health could explore how to incorporate then in core law courses. successful integration of public health into standard law school courses would introduce students to: law's public health context w public health powers w public health inethocls public health's population perspective two criteria must be met, according to the public health literacy conference attendees, if law professors are to adopt public health components in core courses. first, the integmtion must not be too hard to accomplish. materials must be available, and support, in tenns of tine, money, wining, and academic respect, must be forthconling.'o second, faculty must believe that the inclusion of such nuterials will not only be good for public health, but that it will also enhance their students' legal skills and pertiaps legal analysis itself. the reminder of this article seeks to adclress these concerns by exploring more fully the four components of a public health education for lawyers identified above-md examines how to empower law students to be literate in public health, law schools must help them to recognize public health issues and be familiar with the lessons from the law's prior encounters with public health. for over a hundred years, legal scholars have stressed the importance of introducing lawyers to the social, economic, and political context in which the law operates. they have also counseled the value of interclisciplinary analysis. in he path of the luw, for example, justice oliver holmes scolded the legal profession for its belief that law exists apart from the world in which it operates. he argued that lawyers should be trained to understand "the social advantage on which the rule they lay clown must be justified.,."" following in holmes' footsteps in the early twentieth centuly, the legal realists asserted the inipomnce of the facts, out there in the world, to legal analysis. in their "revolt against fonnalism," legal realists suessecl the value of the social sciences and empirical analysis to legal decision making. in subsequent decades, legal scholars from a wide spectrum of perspectives and disciplines stressed the need for interdisciplinary work and social context in order to achieve a rich understanding of the law. scholars and jurists from the conservative "law and economics" school, for example, have focused on understanding the economic context in which the law operates. first, they proclaimed the value of applying economic reasoning to legal decision ~naking.'~ then they recast the analytic tool, useful to explain societal decisions, as an assertion that economic valuation is largely sufficient to comprehend human inotives. from a very different side of the political spectrum, femini~t,'~ critical race, and disability scholars have asserted the importance of teaching law students ahout the g e n d e d , racial, and disability context of legal issues. each group advocates for the inclusion of its issues and disciplines-milyses that shed light on a spectnini of legal issues. repeatedly, we are reminded in rather different ways that law students cannot fully appreciate the meaning or impact of the law unless they understand how it affects different people and reflects critical social phenomena." similarly, we recommend the inclusion of public health analysis and the public health context in which the law operates. public health teaches us that the health or well being of indivicluals is influenced by forces that operate at the population level, beyond an individual's own conm .' risks to health, and the health problems they create, have had a profound influence not only on the lives of individuals, but also shape societies and the structure of our law." to understand not only public health, but the law, students should grasp the public health context in which key legal docuines have developed. students will then recogmze public health issues when they arise, placing them in a fuller and familiar context of similar issues they have studied. they will appreciate more fully the reasons for and implications of the particular doctrines they are mastering. examples from three different areas of the law may serve to demonstrate what we mean by public health context. the first example comes from fourteenth amendment law. virtually every law student studies the infamous case of lochneru. new york, in which the supreme court struck down a state law setting maximum hours for bakeshop workers. o many scholars have viewed lochneras one of the pivotal cases in constitutional law. indeed, many legal theorists regularly cite it when they deride judicial decisions. ' to cry "lochner" is to question the legitimacy of a constitutional decision. lochner, like most important supreme court cases, was about many things and many themes can be dissected the rise of the labor movement;t the supreme court majority's antipathy to progressive labor legi~lation;~~ and the struggle between courts and legislature^.^^ legal scholars, however, seldom discuss the public health context, although the statute at issue was presented by the state of new york as a public health measure and bakeshop workers did experience numerous diseases, including a high prevalence of infectious tubercul~sis.~~ in fact, justice peckhani, writing for the majority of the supreme court, recognized that the statute would have been constitutional if it were indeed, truly, a public health measure. thus, one of the key questions implicit in lochnerwas the meaning of public health and whether worker protection issues could be seen as a valid concern for public health. examined in this manner, lochner provides an interesting insight into the contested nature of public health and the government's role in protecting it. the provision of this context to lochnermay not change a student's ultimate opinion about whether the case was correctly decided, but it may shed new light on the decision. this expanded analysis of lochner would prepare students to understand the ways in which struggles over the scope of public health have helped to weave the fabric of our law. a second example also offers itself from constitutional law, this time relating to the commerce clause doctrine. as numerous commentators have noted, in l~$ezu. united stares, the supreme court r e v d its analysis of congressional power under the commerce clause, making it more difficult for congress to enact regulatory legislation.a this constriction of congressional power appeared to derive, in part, from the court's concern for safeguarding the traditional police powers of the states. underlying that concern was the assumption that police powers constitute a relatively static set of powers, aimed at protecting the public's health and safety, and that these powers have traditionally been the exclusive province of the states. an understanding of public health history, however, makes problematic the notion that public health powers have been or can be the exclusive domain of the statesm real world public health context intrudes. an analysis of public health problems in the modern global environment-from sars ' to the question of youth violence at issue in lopez--raises doubt about the ability of states acting alone to protect the public from such hazards. this analysis does not demonstrate that the supreme court was wrong in lopez-. certainly the coun confronted interpretative and federalism problems beyond the scope of public health, but a discussion of the way in which health problems cross state and even national boarders suggests that lopez' impact may be other than what the court thought. at least, if the court believed that it was protecting the police power and thereby the ability of states to safeguard the health and welfare of their populations, it may well have announced a constitutional rule that will result in exactly the opposite outcome, less protection for the health of a pop~lation?~ this may not prove to be so. but only by providmg students with the public health context behind the case can they huy assess the court's reasoning, speculate on the case's impact, and understand how constitutional doctrines may affect the lives of populations. a final example offered here-although many others can be given--comes from the famous tort case of stubbs v. city of rochester?" the case concerned an outbreak of typhoid fever in rochester, new york. the city offered two different water supplies, one for drinking and one for firefighting. the plaintiffs argued that sewage, known to be in the firefighting water system, contaminated the drinking water supply, causing the plaintiff to conmct typhoid fever. the issue before the court was whether the plaintiff had sufficiently proven that the defendant's negligence caused the typhoid. interestingly, sfubbsconstitutes an early example of a court finding epidemiological evidence sufficient to satisfy the plaintiff's burden of causation. thus the case provides an obvious opportunity to introduce students to basic concepts of epidemiology and to observe how methods for studying disease in populations have changed over the years. this would be useful to students, indeed essential, because tort litigation about product liability and toxic exposures has made epidemiology and public health science central to much civil litigation today, as we discuss later in this ankle.$ but the context of the case goes beyond an analysis of evidentiary issues. the development of clean, municipal drinking supplies is undoubtedly one of the great public health victories of all time. students reading the case should understand that cities did not always supply clean water for drinking and that prior to the introduction of clean water, concenmtion of populations in cities led to extremely high rates of death (especially among children) from diseases such as typhoid fever and cholera.b dr. john snow's study that linked cholem rates in london neighborhoods to the source of people's drinking water persuaded him to remove the handle from the contanlinated broad street pump, and incidentally helped give rise to the modern science of epidemiology.'g before the science of bacteriology learned to identify pathogenic microorganisms in the late th century, municipal authorities, acting on the lessons learned from epidemiology, had achieved a dramatic decrease in deaths from water-borne diseases by protecting drinking water supplies from human wastesa thus .seen in context, sttibbs is not simply about how we can infer individual causation based upon population data, a subject that future ton lawyers would be well advised to master."' stubbs is also a tale from public health's long struggle to use the forces of science and society to protect populations from infectious disease. whether or not the defenclant caused mr. stubbs' typhoid, there can be no doubt that the health of the public benefits from the provision of safe drinking water. but that insight will not be recognized by students who do not know (as many of our students likely do not), that only years ago, deaths from water-borne diseases were common in this country and that it took concerted public efforts to prevent preniatiire death. a second goal is for students to appreciate key legal doctrines that relate to public health, particularly the array of powers government uses to protect the population's health and the restraints the law places upon those powers." all law students cannot be expected to study public health law as preparation for becoming public health lawyers. nevertheless, they should understand the basic contours of how the government, acting through law, organizes to protect and promote the public health and the tensions and challenges created by the exercise of those powers. governments have always taken an interest in the health of their population. from the beginning, concerns about how to protect the population and prevent disease and injury have helped define the role of g~vernment.~) in the united states, activities by the states to promote public health came to form the core of what is known as the "police power." to be literate in public health, and indeed, to ix effective lawyers, law students should be acquainted with the idea of the police power, the limitations applied or suggested to restrain it, and ways that states exercise it. an introduction to the police power will provide students two critical legal strengths: an appreciation of the legal tools available to help carry out public health actions and.a deeper understanding of the law's role in promoting the health of the population. by delving into the police power, students will see first that government activities to promote and protect the population's health have historic roots. they are not an unusual contemporary phenomenon. second, such activities create difficult challenges for our legal system. public health colleagues withwt legal training, although they must use the police power, often lack this depth of understanding. a basic introduction to public health powers would also expose students to the complex role that the federal government plays in matters of public health. it is commonplace to assert that public health lies in the province of the states:s a carefill reading of history, however, demonstrates a critical and expanding federal role in the protection of public health, reflecting threats that exceed the capacity of states. (sonie threats exceed the capacity of national governments as well, such as biotemrism and global epide~nics.)~~ what tools are available for the federal government to ;issure protection of the public heal& the spending power and the commerce clause are most obvious. what doctrinal limitations constrain efforts to protect the health of the public? teaching these issues in their public health context, as we noted above, will enrich the students' understanding of the doctrines and facilitate the students' ability to use the law creatively. the stucly of public health powers can also provide an opportunity to explore the ways that law can be used to advance public goals. law schools usually emphasize private law and individual rights!' our public law courses-~~~s t i t~i t i o~l law, adnlinistrative law, and criminal law-ften highlight the legal rights of individuals and the lhnits of government action. far less discussion time is devoted to the use of the law as a positive instrument, to how governments can act, and the rationales for their action.@ to many lawyers, those questions appear to be outside of the law itself, within the domain of policy or politics. public health law in the core law school curriculum can provide a context for students to understand the broad range and durability of the powers different levels of government wield to protect the public. (such topics already appear in the syllabi of nlany courses in health and environmental law.) in other words, by looking at public health powers, students can become better able to appreciate and use the law positively to advance the public good. no discussion of public health powers would be complete without a consideration of the role that law plays in limiting those powers.@ a broad array of legal doarines, from the substantive due process doctrine developed under the th amendment of the constitution,so to doarines relating to judicial review of administrative agencies, evolved appreciably in the context of public health likewise, some of the earliest equal protection cases challenged actions taken by public health authorities who exercised their powers in a disainlinatory manner?* even today problems may arise when public health agencies use their authority in an unduly coercive or dwnnuna tory manner. lawyers have avenues available to restrain those actions. these topics can engage law students and help them appreciate that law is both a vital engine for public health, and also a critical mediating forre. . . . puellc health mixhod% law students can learn the basic scientific methods that public health employs and in doing so develop a broader acquaintance with quantitative and empirical techniques that are critical to the contemporary practice of law. the public health, conference noted that "public health draws on all the scientific knowledge that informs our understanding of how humans interact with their environments and manifest disease and injuries."s epidemiology, which studies the incidence, prevalence, distribution, and etiology of disease, is the core discipline of public health. epidemiologists rely upon a variety of experimental and observational studies, statistical and analytic methods. lawyers cannot be expected to become epidemiologists. to understand the public health issues, however, they should have a basic grasp of the quantitative and scientific methods on which epidemiology rests. at minimum, lawyers should understand the types of studies that epidemiologists rely upon,% possess a familiarity with the concepts of rates, incidence, and prevalence; be aware of the distinctions between association and causation; and recognize that there are many ways that epidemiologists infer causation from a s s~c i a t i o n .~~ lawyers might also receive a basic introduction to scientific reasoning,% the ways in which scientific consensus is developed,s and the distinctions between legal and scientific notions of "causation" and "truth."% (ironically, most scientists themselves simply do science, remaining unfamiliar with studies of science and scientific methods.") the suggestion that lawyers should be better informed about statistics and science is neither new nor exclusive to proponents for public health literacy. critics of the legal system's use, misuse, or abuse of science and scientists have long lambasted lawyers for their ignorance about what science is and how it works. @' a supreme court decision, dauben v. merrell dow pbumacmticak, lnc., and its progeny have made the debate central to tort litigation in the united states. z in daubert, the supreme court reconsidered the standards for admission of expert evidence. rejecting the earlier fty@ nile as incompatible with the federal rules of evidence, the court instead required federal judges to act as gatekeepers and determine whether the proffered evidence was "reliable," which the court claimed, required a determination of whether the evidence was based on a scientifically valid methodology.& in daubertitself, two justices questioned the wisdom of asking federal trial judges to take on the role of deciding what is good science and what is not, describing the task as akin to asking them to become "amateur ~cientists."~~ since daubert, however, in federal coum and many state coum, that is just what has happened.& because expert witnesses may offer opinions about causation that qijantwative and sceniwic reas ni"ln are thought to be useful to the finder of factjury or j u d g e a trial judge is now required to act as a "gatekeeper" and decide which expert testimony to admit. the daubert process-pretrial hearings on the admissibility of expert testimony-now donlinates product liability and toxic tort cases ' recently, the data quality act has extended a daubert-like process into federal agencies, providing an opportunity to challenge the science used in setting agency policy and in regulatory decision making. this means that every lawyer working with or in government agencies will need to understand science and quantitative reasoning as never before. all these procedures hinge on how lawyers understand and portray science, an important reason why an introduction of public health and scientific decision making is necessary in the core cumculum law school. lawyers employing the daubertprocess have spawned a vimal industry designed to inform judges and lawyers about the "abc's" of epidemiology, the scientific method, and statistics.@ these legal pundits on science have expanded on the court's suggestions in daubert, creating a check-list approach to assessing whether scientific testimony is relevant and reliable, confusing-often deliberately-the legal concept of causation with how scientists reach conclusions about little or none of this lawyers' rendition of science has been subjected to scholarly scrutiny by scientists, and legal practitioners and judges, largely uneducated about science and quantitative methods, have wandered far from scientific practice." the need for a better understanding of science among lawyers is now plainly evident. justice breyer, in his influential critique of the regulatory process and administrative law, has called for a more rigorous understanding of quantitative analysis, including cost-benefit analysis, in determining regulatory standards." the national academy of sciences has a committee of scientists and lawyers reviewing these issues. in light of daubert, lawyers must be better informed about how scientists assess causality, how they value evidence, and the application of epidenuology, toxicology, animal and clinical studies. thus, there is an urgent need to develop cumculum within law schools that teaches law students to understand quantitative science. and what better way than around public health issues, that are already deeply embedded in the law? it would meet the broader goal of ensuring that lawyers are competent consumers of epidemiological and statistical analyses and that lawyers can work collaboratively and intelligently with public health professionals, medical expew, regulators, and the plethora of other professionals who rely upon quantitative and empirical tools. lawyers should be able to think critically about populations and what it means to focus on them, as opposed to individuals. this approach to legal problems contrasts with the law's usual focus on individuals. drawing on the traditions of anglo-american liberalism, our jurisprudence posits individuals as mini-sovereigns, each replete with her or his own endogenous set of preferences and from this premise, the goal of law becomes regulation of the interaction of those mini-sovereigns; to protect their rights and property; and, for those who subscribe to utilitarian or neo-classical economic theories, to maximize their aggregate utility or wealth. law schools, with their typical emphasis on competition ancl non-collaborative work, reinforce the individualism evident in the doctrines this foundational individualism manifests itself in and deeply influences many fields of law. a few bwad-brushed examples may demonstrate the point. the field of health law itself, as john v. jacobi observed, concerns itself with "bilateral disputes over health finance, medical injury, and patient's rights...'" what is missing, he argues, are the "tools or the perspective" to address issues that affect populations. american constitutional law, too, is famously devoted to analysis and consideration of the rights and interests of individuakn thus the question of whether a woman can have an abortion is framed as a conflict between a woman's right to privacy versus the rights of the individual fetus. o the law of race discrimination, which was once understood as recognizing and responding to group harms:' focuses significantly on the needs and interests of individuals, rather than groups!* although the supreme court's recent decision to uphold race-conscious decision making by universities signals some recognition of the importance of group perspectives,b it remains me that state policies that disparately disadvantage suspect classes are not held to violate the constitution even if' the disadvantage to the group is clear and obviously foreseeable.& only when the state, anthropomorphized as if it were also an individual, intentionally aims at disadvantaging one or more people on the basis of their membership in a suspect class, is the constitution found to be offended.us even tort law, the field of common law most focused on population-based concerns, remains heavily influenced by individualism. as scholars have noted, traditional tort law, prior to the so-called ws "torts revolution," assumed that "individualism outranks concerns for others."& these tenets remain ensconced in the field, for example, in the noduty rule that many states continue to affirm!' perhaps the single most influential critique of traditional tort law emerges from scholars and judges who believe that the primary goal of tort law should be the maximization of economic efficiency.w while this position postulates the the dominating individualism of american law has come under sustained critique in recent decades from: fenunist scholars who postulate the importance of relationships;w critical race scholars who point out the need to understand the position of identity groups;" ancl communitarians who stress the primacy of nevertheless, these critics, remain just that: critics of the prevailing regime. their influence is occasionally evident in case law, but they have largely failed to alter the status quo. perhaps even more impoitantly, as david ortiz has noted, in many subtle but fundamental ways these critics share many of the individualistic premises of the jurisprudence they critique ~-ofien reifying groups or communities, treating them as if they were, in essence, individuals. what the critics,of individualism in the law seldom offer is a serious or sustained examination of groups (other than identity groups), which includes an analysis of them and their interests and their relationships to the individuals who fonn them. this, of course, is precisely what public health and its scientific foundations do. as jacobi writes, "[plublic health is a discipline dedicated to the scientific examination of the conditions affecting the health of populations." public health's prinlary sciences-epidemioiogy and biostatistics-focus on populations as populationsb and apply empirical, statistical, and analytical methods to understand how to define them, determine what affects them, and what distinguishes them from other populations, and how they relate to the individuals who comprise them. by comparing populations, epidemiologists have garnered ,insights useful to legal analysis. geoffrey rose explains that how populations are selected affects what can be learned.* for example, if we try to understand the causes of coronary artery disease by comparing people in a particular population who have heart attacks with those who don't, we may identlfy a risk factor, such as exercise, the presence of which differs between the groups. however, unless the population as a whole is compared with other populations, we may easily miss causes of the disease to which everyone in the population was exposed. only by many comparisons of many populations with different rates of disease, can be begin to idenufy all of the factors contributing to disease? ' rose's insights raises several points relevant for legal analysis.* first, he demonstrates how a focus on individuals-usually the symptomatic p a t i e n w a n at times obscure our understanding of what is happening to the larger group. thus the health damage done to the population by asymptomatic or untreated individuals with mildly elevated blood pressure is far greater than the sum of damage done to symptomatic individuals and those found by doctors to the journal of law, medicine & etbics have hypertension, for the latter group is much smaller. can changes in the environment affect the prevalence and distribution of hypertension in the population? only by comparing groups can scientists predict how individuals are likely to respond to elements of their social and physical environments. this is relevant to a number of legal issues. for example, in understanding the nature and impact of discrimination, we may recognize that the phenomenon at a population or social level cannot be well understood simply by looking to discrete cases of discriminatory behavior. indeed, epidemiological studies that have associated the relationship between discrimination in a population and the health status of minorities suggest precisely that point. epidemiology also teaches that the risks individuals face are significantly affected by their environment. for example, an individual with a low genetic predisposition to a disease may still be at a higher risk of that disease than an individual with a high genetic predisposition if the former is exposed to a more dangerous social and physical environment, where the incidence of the disease is tugher. from this we learn that even if our goal is to change an individual's risk factors, environmental or population-based interventions may be more successful than those policies that seek to change individual risk factors. epidemiology's analysis of the relationship between individuals and social risk also has relevance for a wide range of legal issues. for example, debates about whether government should enact apparently paternalistic laws, such as those requiring motorcycle helmet laws, often presume that individuals can make independent choices and that they can control the probabilities of their being affected by different risks.'" rose's work questions that assumption and provides legal decision makers with a different perspective for analyzing so-called paternalistic laws. on the one hand, a seat belt law niay not actually be paternalistic, if we recognize that inciivicluals cannot in fact control the risks to which they are exposed. on the other hand, such laws may be inefficient ways of reducing highway deaths if in fact they focus on altering individual rather than population behavior. as beauchamp and steinbock argue, "[tlhe population perspective constnicts a new story about how highway injuries occur in likewise, a population-based perspective may alter the way we understand relatively new issues, such as the legal responsibility of the food industry for the growing obesity epidernic.lo the traditional individualism of american law (and culture) would suggest that in the absence of misrepresentation or the sale of an exceptionally dangerous product, the food industry should not be viewed as responsible for the pr b em.l~~ individuals should be regarded as free and responsible for their own eating and exercising habits as well as the weight gain that ensues.""' a population-based perspective, however, questions whether individuals should be viewed as personally responsible for their own weight. after all, the prevalence of obesity is increasing both across the broad u.s. population and across varied sub-populations.iw likewise, the health damage stretches across the population, harming individuals who do not consider themselves in need of weight control or who do not meet the official definition of obesity (bmi greater than ). in fact, more health damage is likely occurring in the part of the population not identsed as overweight than in the overweight population.' this suggests that causes must be understood at a broad, population level. something is happening to make millions and millions of people make "choices" that lead to their gaining weight. epidemiologists, therefore, are looking to fundamental environmental changes, including the marketing and distribution of food, as well as the way our built environment affects our activity levels.' these deeper causes may suggest legal causation should be seen as residing in those parties (corporate and governmental) that perpetuate the obesity-causing environment, or it may suggest a role for affirmative government interventions to alter the environment.im while adoption of a populationbased perspective does not provide a single or simple determinative analysis of where and how the law should assign responsibility and intervene in the case of obesity, it does suggest a different set of remedies and approaches than would be offered by a more individualistic, marketbased approach, which might focus solely on remedying market failures by giving individuals more information on how to make healthy choices. importantly, epidemiology also teaches us that populations differ and that it is critically important to define and compare them. thus in thinking about obesity, or any other issue, we need to take care to consider what constitutes the population at issue. lawyers, however, often use terms like "the public good" or "majority" without defining the group or assessing how one group differs from others. this lack of precision may inappropriately privilege majorities (as may occur when courts uphold drug testing for school children on the unproven assumption that it is in the public interest),iw or it may devalue their interests by simply not treating them with sufficient rigor and import. a population-based perspective would not necessarily lead a judge either to uphold or bar a drug search, but it would demand that the "public" cited in defense of the search would be carefully delineated and the relationship between it and the search would be articulated. ultimately, a population-based perspective offers valuable lessons about the complexity of the relationship between individuals and populations. the history of public health is replete with examples in which individual interests have conflicted with either real or purported interests of particular publics. however, public health also teaches us that not only are individual interests interwoven with public conditions,"l but that recognition and protection of individual interests may also at times be the most efficient ways to secure a common good. early in the aids epidemic, it was noted that societies that respected individual rights were often the same ones which achieved individual behaviors most protective of tlie whole population."* (wealth and security, it should be said, often predate individual rights and explain tlie ability of people to lean and change behavior.) these perspectives from public health are important to understancling laws (statutory, regulatory, and common law) that purport to serve the common good. in almost all such cases, a lawyer's understanding of the population perspective will add to and enrich the legal analysis. whether drafting an administrative regulation to control air pollution levels or litigating a class action employment case, a lawyer's ability to take populations seriously and recognize the dynamic and multivariate relationship they have to individuals will improve the analysis. the true integration of piiblic health into legal education will not be easy to achieve. law schools have for the most part been quite reluctant to embrace change."' pressures from bar examiners iindoubtedly exacerbate that recalcitran~e."~ in addition, curricular changes require an investment of faculty time, that they may well be unwilling to make without sufficient institutional scippo~t."~ the most critical factor, however, may ix the existence, or lack thereof, of :in engaging :incl intellectu:rlly stimulating body of scholarship using the insights of public health to address a range of legal issues. attendees at tlie public health literacy for lawyers conference agreed that public health will not be integrated into the core legal curriculum unless and until a hotly of legal scholarship demonstrates its relationship to law and its power to enhance legal analysis. if such ;i body exists, then there is reason to hope that law professors will take note. neo-classical economics, for example, became part of legal education only after scholars, such as ronald coase and richard posnerl" produced scholarship that displayed the ability of neo-classical economics to provide a coherent, iinsed, descriptive, ancl nomtive analysis of a wide-range of legal problems. the breadth and apparent elegance of their approach helped to stimulate excitement and debate among legal scholars, spurring additional scholarship on the role of economic reasoning in the a s a result, even critics of the distributional consequences of law and econonucs came to see econoniic analysis of tlie law :is a perspective and skill that their students "ought" to know. to permeate legal education with population-based legal analysis, a similar scholarly revolution investigating the utility of incorporating concepts from public health science is needed. perhaps it has already begun. in recent years, there has been a renewed interest in public health law (including this secondjlmesyniposiiim). book-length expositions of the field have been and seven major conferences have been held. in addition, issues such as bioterrorism has spurred considerable scholarly delxtte.'" but few scholars have consciously attempted to explore the broader utility of population-based analysis for law and jurisprudence. perhaps, one by one, cases and courses iiiust be reexamined to assess the value of population-based legal analysis. to reach a wider audience, and to entice a critical mass of scholars to join the debate and bring it to their students, more and in-depth scholarship is certainly needed. as we noted at the start, public health's focus on populations, resting on the science of epidemiology, provides a valuable prism for understanding the relationship of individuals and groups and the ways that laws can and ought to affect the~ii.'~' in addition, analyses of morbidity and mortality, and health measures, may well provide an important complement or even alternative to wealth maximization as a measure for determining utility for a population.' grounded in observation ancl association, rather than on a singular deductive construct, public health science is unlikely to offer the kind of elegant, unified theory for human behavior spelled out in neo-classical economics, a theory that reminds us of h.l. mencken's suggestion that "for every problem, there is one solution which is simple, neat and wrong." nevertheless, public health can provide an alternative way of looking at old legal issues. for example, it may help lawyers analyze key issues, such as what constitutes the public good, and what are the proper roles and powers of government, where current answers are not wholly satisfactory. in order for public health to play this role, more scholars must join the field. they must explore and debate what it means to consider legal issues through the prism of public health. we expect that once they take up that baton, they will find that it leads them down interesting and as yet unpredictable paths. we hope they will join us on that journey. references see, e.g., guide to comintinity preuentimseryices, at <http://www.thecoi~iiiinityguide.org> (last visited october , ) (showing legal interventions as among the most effective proven interventions for community health). in recognition of this, the centers for disease control and prevention established a public health law program in w. see centers for disease control and prevention, hcblic heulth luw progrum, at <http://www.plippo.cdc.gov/od/ phlp/almiit.asp> (last visited october , ) . a. robbins and p. freeman, "public although we dmw from the discussions at the april conference, the views and errors here are solely are own. a list of jd/mph programs appears at cdc, public health program, public health practice program ofice, training and education in public health law, at <www, phppo.cdc.gov/od/phlp/education.asp> (last visited october , ) . for a discussion of the growth of combined degree programs in generdl, see l.r. crane, "interdisciplinary combined-degree and graduate law degree programs: history and trends," john marshall law . . rw~uu, ( ): - . . goodman, supra note , at - . see university of the pacific, mcgeorge school of law, capital center, bioterrorism, national security & public health law initiative: models for teaching, at <http:// www. mcgeorge.edu/government-law-and-policy/ bioterrorism/models-for-teaching.htm> (last visited october , ) . the public health advocacy institute, intends, as part of its public health literacy for lawyers project, to produce model materials for one or more core law school courses. m. minow, "education for co-existence," arizona why justice is good for our health: the social determinants of health inequalities uniuersity of chicago law review lochner the rise and fall of the constitutionalization of public health judicial power and reform politics: he anatomy of lochner v the role of new federalism and public health united states v. lopez judicial review under the commerce clause inside the federalism cases: concern about the federal courts parmet supra note judicial review of fda authority to regulate tobacco products as "drugs ( ) (city violated the fourteenth amendment when in the name of public health public health literacy for luwpts: selecting the content, paper presented at public health litmcy forluwym how science works epidemiology, justice, and the probability of causation burden of proof: judging science and protecting public health in (and out od the courtroom a fish out of water: scientisrs in court shattuck lecture -evaluating the health risks of breast implants: the interplay of medical science, the law, and public opinion galileo'sreuenge: junk science in the courtroom see also kuinho tire co complex litigation at the millennium: upsetting the balance between adverse interests; the impact of the supreine court's trilogy on expert testimony in toxic tort litigation is science different for lawyers . the science, technology and law panel created by the policy division of the national research council was established to "bring the science and engineering community and the legal community together law, politics, and the claims of community rights talk: xbe impoverishment atoinism the the y of hgtilation of civil government: two treatises feminist perspectives and the ideological impact of legal education on the profession thinking beyond my own interpretation: reflections on collaborative and cooperative learning theory in the law school book review -lawrence . gostin's seton half law review groups and the equal protection the failure of gender equality: an essay in constitutional dissonance individual rights and class discrimination: the fallacy of an individualized determination of disability , (striking down admissions program for state university in which applicants were given specific admissions points based upon their race) holding that state policy that foreseeably disadvantaged women did not violate the constitution) holding that police exam that disparately excludes african american applicants from police force does not violate the constitution unless the defendant city intended to discriminate) scientific policymaking and the tom revolution: the revenge of the ordinary observer prima facie torts, combination, and non-feasance at (attributing the nile to an ideology of individualism). the most iduential scholar/judge advocating this view has been judge richard posner science, reason, csr ton law hateful speech, loving communities: why our notion of "ajust balance philosophy and the human sciences: philosophical p a p , wl spheres of justice: a oefense of pluralism and stanford law jacobi, supra note he strategy of premniim medicine integrating law and social epidemiology twenty-five states have repealed mandatory helmet laws for motorcycle riders over twenty-one years of age since the highway safety act of removed the department of transportation's authority to condition federal highway hnding on helmet-use laws. national highway safety administration ) (noting that obesity has become an epidemic in the united states and listing associated liealth problems). the public health advocacy institute using the absurdity of regulating the marketing of fast food because of its impact o n obesity as a justification for denying the state the right to regulate the marketing of tobacco) macdonald's ing that consumers could not bring a claim against macdonald's holding it responsible for their weight, as their decision to eat there was their own free choice ) (holdmade by the center for consumer freedom, an industrysupported group that objects to legal liability for the food industry the gorge yourself environment public health service, ofice of the surgeon general, he surgeon general's call to action to prevent and decrease ooenoeight and obesity the ideal population policy would be a substantial and general weight reduction environmental conuibu-' tions to the obesity epidemic for a discussion of the relative merits and demerits of tort litigation and regulatory approaches to public health, see the relationship between student illicit drug use and school drug-testing policies medicine and public health, ethics and human rights the problem of social cost the firm, the market, and the law he economic structure of tort law the ecoiiomics oflustice economic analysis of laui the inefficient common law is wealth ;i value problem-solving behavior and theories of tort liability public health pmcfice bioterrorisni, public health and civil liberties public health law in the age of terrorism: rethinking individual rights and common goods see text accompanying note supra. . this is not to say that any of these measures can or should be the sole way of judging welfare maximization, but they do provide an interesting alternative to the economist's tendency to reduce all issues to questions of wealth key: cord- -dao kx authors: rife, brittany d; mavian, carla; chen, xinguang; ciccozzi, massimo; salemi, marco; min, jae; prosperi, mattia cf title: phylodynamic applications in (st) century global infectious disease research date: - - journal: glob health res policy doi: . /s - - -y sha: doc_id: cord_uid: dao kx background: phylodynamics, the study of the interaction between epidemiological and pathogen evolutionary processes within and among populations, was originally defined in the context of rapidly evolving viruses and used to characterize transmission dynamics. the concept of phylodynamics has evolved since the early (st) century, extending its reach to slower-evolving pathogens, including bacteria and fungi, and to the identification of influential factors in disease spread and pathogen population dynamics. results: the phylodynamic approach has now become a fundamental building block for the development of comparative phylogenetic tools capable of incorporating epidemiological surveillance data with molecular sequences into a single statistical framework. these innovative tools have greatly enhanced scientific investigations of the temporal and geographical origins, evolutionary history, and ecological risk factors associated with the growth and spread of viruses such as human immunodeficiency virus (hiv), zika, and dengue and bacteria such as methicillin-resistant staphylococcus aureus. conclusions: capitalizing on an extensive review of the literature, we discuss the evolution of the field of infectious disease epidemiology and recent accomplishments, highlighting the advancements in phylodynamics, as well as the challenges and limitations currently facing researchers studying emerging pathogen epidemics across the globe. electronic supplementary material: the online version of this article (doi: . /s - - -y) contains supplementary material, which is available to authorized users. globalization has dramatically changed the way in which pathogens spread among human populations and enter new ecosystems [ , ] . through migration, travel, trade, and various other channels, humans have and will continue to intentionally or unintentionally introduce new organisms into virgin ecosystems with potentially catastrophic consequences [ ] . humans are not the only culprits, however; global climate pattern changes can alter local ecosystems, creating favorable conditions for the rapid spread of previously overlooked or even undiscovered organisms among humans, giving rise to unexpected epidemics [ , ] . recent years have been marked by global epidemics of ebola, dengue, and zika, derived from pathogens previously restricted to local outbreaks [ ] . according to the world health organization, more than one and a half billion people are currently awaiting treatment for neglected tropical diseases with similar potential for global spread, for which we have limited knowledge of etiology and treatment options [ ] . this lack of knowledge further limits our ability to investigate the putative role of these pathogens in future epidemics or even pandemics. epidemiological strategies have been and still are the first line of defense against an outbreak or epidemic. despite conventionality, traditional epidemiological methods for the analysis of global infectious diseases are subject to errors from various sources (fig. ) and are thus often inadequate to investigate the epidemiology of an infectious disease. putative outbreak investigations typically ensue following case notification of one of the diseases recognized by local and global public health organizations. trained investigators subsequently collect data on cases and diagnoses to establish a disease cluster. during active surveillance, more cases may be detected through outreach to healthcare facilities and nearby health departments. relevant case contacts, such as family, friends, and partners, are also sought to provide details on demographics, clinical diagnoses, and other potential risk factors associated with the spread of the disease [ ] . however, the lack of infrastructure, trained personnel, and resources in low-and middleincome countries are prohibitive against field epidemiology investigations, as contact tracing and surveillance both require systematic, unbiased, and detailed investigations. the reconstruction and interpretation of transmission networks are often very sensitive to response, selection, and recall biases and are strictly limited by surveillance data collected in many regions with diverse socioeconomic and cultural backgrounds [ ] [ ] [ ] . in addition, even with a highly effective surveillance system, environmental, zoonotic, and vector-borne transmission dynamics confound analysis by shadowing alternative (i.e., not human-to-human) routes of disease acquisition. furthermore, routine analyses of pathogen subtype and drug resistance are conducted only in a subset of developed nations, wherein variation in screening assays and protocols and therapy regimens increases the discordance in surveillance [ , ] . despite the limitations to traditional infectious disease epidemiology, major advances in study designs and methods for epidemiological data analysis have been made over the past decade for a multifaceted investigation of the complexity of disease at both the individual and population levels [ , ] . however, many challenges for infectious disease research remain salient in contemporary molecular epidemiology, such as the incorporation of intra-and inter-host pathogen population characteristics as influential factors of transmission. combating current and future emerging pathogens with potential for global spread requires innovative conceptual frameworks, new analytical tools, and advanced training in broad areas of research related to infectious diseases [ ] [ ] [ ] . an expanded multi-disciplinary approach posits advancement in infectious disease epidemiology research and control in an era of economic and health globalization [ , , , ] . fortunately, recent developments in phylogenetic methods have made possible the ability to detect evolutionary patterns of a pathogen over a natural timescale (months-years) and allow for researchers to assess the pathogen's ecological history imprinted within the underlying phylogeny. when reconstructed within the coalescent framework, and assuming a clock-like rate of evolution, the evolutionary history of a pathogen can provide valuable information as to the origin and timing of major population changes [ ] . phylogenetic methods also provide key information as to the evolution of both genotypic and phenotypic characteristics, such as subtype and drug resistance (fig. ) . even though phylogenetic methods are also limited in certain areas, such as restriction of analysis to only the infected population, a significant subset of these limitations can be overcome by complementary use of data from surveillance (both disease and syndromic) and monitoring [ ] (fig. ) . by integrating phylogenetic methods with traditional epidemiological methods, researchers are able to infer relationships between surveillance data and patterns in pathogen population dynamics, such as genetic diversity, selective pressure, and spatiotemporal distribution. systematic investigation of these relationships, or phylodynamics [ ] , offers a unique perspective on infectious disease epidemiology, enabling researchers to better understand the impact of evolution on, for example, spatiotemporal dispersion among host populations and transmission among network contacts, and vice versa [ , ] . the study of the interconnectedness of these pathogen characteristics was previously limited by the cost and timescale of the generation of molecular data. recent decades have been characterized by technology with the ability to rapidly generate serial molecular data from identifiable sources for which we can obtain detailed relevant information through epidemiological surveillance, allowing for the merging of phylodynamics and epidemiology, or evolutionary epidemiology [ , ] . hence, progress in the field of molecular evolution has provided the opportunity for real-time assessment of the patterns associated with local, national, and global outbreaks [ ] , cross-species transmission events and characteristics [ ] , and the effectiveness of treatment strategies on current [ ] and recurring epidemics [ ] . these assessments are essential for monitoring outbreaks and predicting/preventing pandemic inception, a good example being the recent study of middle east respiratory syndrome coronavirus global transmission [ ] (additional file (video s )). but has the, field of evolutionary epidemiology quite reached its full potential? in this article, we systematically discuss how the application of phylodynamic methods has and will continue to impact epidemiological research and global public health to understand and control infectious diseases locally and across the globe. in a strict sense, the concept of phylodynamics is anything but new. the phylogenetic tree reconstructed by haeckel in using phenotypic traits [ ] was used to explain the distribution of the earliest humansthe "twelve races of man"-across the globe and the location of the "centre of creation." this incorporation of both spatial information and phylogenetic relationships in the inference of population distributions and diversity among geographical locations is a branch of phylodynamics, often referred to as phylogeography. since then, the progression of genetic sequencing technology as well as geographical information systems (gis) has enabled evolutionary biologists to gain a higher resolution view of infectious disease dynamics. the st century, in particular, has witnessed unparalleled advances in methods and techniques for molecular sequence data generation and analyses. however, the relationship of progress and perfection is far from linear, along with its relationship to navigational ease. for example, phylodynamic inference has transitioned into a highly statistics-focused process with the corresponding challenges, including informative samples that can significantly affect the accuracy of results [ ] [ ] [ ] . several research groups [ , ] have reviewed and/or demonstrated the impact of neglecting critical quality control steps on obtaining reliable inferences using the recently developed phylodynamic frameworks, particularly with high throughput, or next-generation, sequencing (ngs) data. some important steps include ensuring uniform spatial and temporal sampling [ ] , sufficient time duration between consecutive sample collections for observing measurable evolution [ ] , coverage of deep sequencing, and consideration of genomic recombination [ ] . the reliance on phylodynamic methods for estimating a pathogen's population-level characteristics (e.g., effective population size) and their relationships with epidemiological data suffers from a high costincreasing the number of inference models, and thus parameters associated with these models, requires an even greater increase in the information content, or phylogenetic resolution, of the sequence alignment and associated phenotypic data. low coverage [ ] and the presence of organism-or sequencing-mediated recombination [ ] , can skew estimates of the evolutionary rate and even impact the underlying tree topology, particularly when dealing with priors in the bayesian statistical framework commonly used for phylodynamic inference. programs such as splitstree [ ] can take as input a nucleotide alignment and output a network in which the dual origins of recombinant sequences are displayed in a phylogeneticlike context. however, network-reconstructing programs have difficulty distinguishing actual recombination events from phylogenetic uncertainty, and branch lengths do not usually reflect true evolutionary distances [ ] . despite much work ongoing in this area, there are currently no broadly applicable methods that are able to reconstruct phylogenetic network graphs that explicitly depict recombination and allow for phylodynamic inference. although the bayesian framework has shown to be fairly robust with the inclusion of recombinant sequences in large population studies [ ] , the inclusion threshold has not been thoroughly investigated and is likely dependent on a number of factors, such as sample size and sequence length. recombinant sequences are thus usually removed prior to analysis; however, the ability to incorporate recombinant sequences is imperative given our knowledge of the role of recombination in virus adaptation [ ] , for example. more details on methods that can potentially account for recombination, applicable to a variety of pathogens, are discussed by martin, lemey, & posada [ ] . while the traditional realm of phylogenetics has focused on rapidly evolving viruses, the development of whole-genome sequencing (wgs) has made possible the expansion of phylodynamic methods to the analysis of slower-evolving microorganisms, such as bacteria, fungi, and other cell-based pathogens. wgs has widened the range of measurably evolving pathogens, allowing for the identification of sparse, genetically variable sites, referred to as single nucleotide polymorphisms (snps), among populations sampled at different time points. the use of wgs in phylogenetics is highly beneficial not only in resolving relationships for slower-evolving organisms but also in reconstructing a more accurate evolutionary history (phylogeny) of an organism, rather than the genealogy (single gene), which can differ significantly from the phylogeny due to the presence of selective pressure or even genetic composition [ ] . however, as with phylodynamic analysis of rapidly evolving viruses, wgs analysis of cell-based pathogens comes with its own challenges, as discussed in detail elsewhere [ ] . implementation of phylodynamic and/or phylogeographic analysis has transitioned over the last two decades from maximum likelihood to the bayesian framework. this framework provides a more statistical approach for testing specific evolutionary hypotheses by considering the uncertainty in evolutionary and epidemiological parameter estimation. given surveillance data (e.g., the duration of infection) and the specification of an epidemiological mathematical model, bayesian phylogenetic reconstruction can also be used to estimate epidemiological parameters that might otherwise be difficult to quantify [ ] . for example, during the early stage of an epidemic, wherein the pathogen population is growing exponentially, the rate of exponential growth can be estimated from the phylogeny using a coalescent model that describes the waiting time for individual coalescent events of evolutionary lineages. this rate estimate can be combined with knowledge of the duration of infection for a particular pathogen to estimate the basic reproduction number, r (e.g., [ ] ), as well as the prevalence of infection and number of infected hosts. transmission dynamics can similarly be inferred following the early exponential growth of the pathogen, during which the pathogen has become endemic. estimation of these parameters is described more thoroughly in volz et al. [ ] . with the expansion of phylodynamic methods to global epidemics, theoretical studies have found that inferences of infection dynamics within the coalescent framework are limited by the assumption of a freely mixing population [ ] . this assumption is often violated with the inclusion of several isolated geographical areas with single or few pathogen introductions. without considering this factor, population structure within a phylogeny can severely bias inferences of the evolutionary history and associated epidemiological parameters [ , ] . to overcome this limitation, software packages such as beast (bayesian evolutionary analysis sampling trees) [ ] [ ] [ ] have recently developed algorithms that allow for the integration of coalescent, mathematical, and spatial diffusion models [ ] [ ] [ ] [ ] [ ] [ ] . more importantly, beast readily implements a comparative phylogenetic approach, which incorporates parameterization of phenotypic trait evolution to identify predictors of population dynamics and spatial spread, all of which are estimated/assessed simultaneously during reconstruction of the evolutionary history [ , ] . statistical evaluation of the risk factors for pathogen population growth and spread can be performed concurrently with the assessment of phylogenetic resolution within the data [ ] , discussed above as a challenge to complex phylodynamic analyses. for example, in the absence of strong phylogenetic resolution, bayesian statistics are more sensitive to long-branch attraction bias [ , ] , wherein rapidly evolving lineages appear to be closely related, regardless of their true evolutionary relationships. this phenomenon, therefore, influences inferences of spatiotemporal spread of the studied pathogen, as well as estimation of the relationship of pathogen population behavior with potential risk factors, such as climate change, host and/or vector distribution, accessibility and so on. the influence of low-resolution molecular data on the reliability of phylodynamic inferences highlights the importance of the implementation of the method described by vrancken et al. [ ] , or even a priori estimation of the phylogenetic and temporal resolution (sufficient time between sampling) [ , ] . unlike other phylogenetic frameworks, bayesian inference enables utilization of prior knowledge in the form of prior distributions (in combination with information provided by the data); however, abuse of prior knowledge is possible and can lead to incorrect conclusions. even within the bayesian school of thought, scientists do not always agree with regard to the specification of prior distributions under certain conditions. the incorporation of prior information is, however, intuitively appealing, as it allows one to rationalize the probability of an estimate based on previous knowledge of the typical behavior of the parameter among populations of the organism under study. but what can we do if we have no knowledge regarding a particular organism or population? this has become a more pertinent issue recently with the increasing rate of discovery, facilitated by ngs, of organisms for which we have limited prior knowledge, such as novel viruses and bacteria, [ ] . one of the advantages of the bayesian phylodynamic approach is the ability to test multiple hypotheses regarding the evolution or epidemiological models used to describe infectious disease behavior, but because of the intricate relationship of these models, reliable inferences require testing of all combinations of the individual proposed models. although often neglected due to computational complexity, improved estimates of marginal likelihoods used for statistical model comparison have been demonstrated with less computational effort [ ] . additionally, if we know that we know nothing about the parameter in question, then, in fact, we know something. referred to as the "objective bayesian" approach, this ideal allows researchers to alter a normally "subjective" prior to create one that is minimally informative. this term is used because the impact of this type of prior on parameter estimation can be controlled to a minimum, allowing the data to dominate the analytical process and conclusions drawn [ ] . although similarly appealing, this approach can be particularly problematic with small datasets [ ] or biased datasets, such as the exclusion of potential intermediate sampling locations [ ] . the expanding volume of sequence data and increasing efforts to combine epidemiological and laboratory data in open access locations can help to improve evolutionary estimates. additionally, the growing availability of data and collaboration can accelerate our understanding of the emergence and spread of infectious diseases through coordinated efforts by multidisciplinary researchers across various institutions and public health organizations. more detail on the benefits of open access databases and data sharing in the context of phylogenetic epidemiology is reviewed in [ ] and [ ] . combining pathogen genetic data with host population information (e.g., population density and air traffic) in a statistical framework is critical for the reliable assessment of factors potentially associated with pathogen population dynamics and geographic spread. the comparative phylogenetic approach described above [ ] was used recently to identify potential determinants of the dengue virus (denv) introduction to and spread within brazil. results from nunes et al. [ ] suggested that for three denv serotypes, the establishment of new lineages in brazil had been occurring within to -year intervals since their primary introduction in , most likely from the caribbean. additionally, they observed that aerial transportation of humans and/or vector mosquitoes, rather than distances between geographical locations or mosquito (particularly aedes aegypti) infestation rates, were likely responsible. the study by nunes et al. marked one of the first uses of the comparative phylogenetic approach for vector-borne tropical diseases and implies the need for a similar approach in future studies aimed at investigating transmission patterns of a broad range of emerging vector-borne viruses. for example, this approach will allow researchers to determine if specific universal factors, such as vector species, are predictive of global transmission route or if health policy and prevention strategies tailored specifically to the pathogen, irrespective of the vector, are required for effective control. with the development of molecular clock models for serially sampled data [ ] , phylogenetic analyses have helped to uncover the timing of transmission events and epidemiological origins. moreover, when paired with comparative phylogeographic models, researchers have been able to identify risk factors most likely associated with these particular events. since the inception of the zika virus (zikv) pandemic around may of in brazil [ ] , phylogeneticists and epidemiologists have sought to reveal mechanisms by which zikv has spread and the factors fueling the wide geographical leaps. a full-genome phylogeographic analysis of zikv isolates collected during - revealed very intricate spatiotemporal transmission patterns across africa prior to the introduction into asia [ ] . from its origin in uganda, two independent transmission events appeared to play a role in the spread of zikv from east africa to the west circa : the first involved the introduction of zikv to côte d'ivoire with subsequent spread to senegal, and the second involved the spread of the virus from nigeria to west africa. results from spatiotemporal analysis demonstrated that uganda was the hub of the african epidemic as well as the common ancestor of the malaysian lineages sampled during the outbreak [ ] . following the emergence and rapid spread of zikv in brazil and other south american countries [ ] , faria's group sought to further characterize the spatiotemporal dynamics of zikv following introduction into this region [ ] . in addition to sequencing data, air traffic data for visitors to brazil from other countries associated with major social events during - were included to test different hypotheses of airline-mediated introduction of zikv in brazil. the results linked the origin of the brazilian epidemic to a single introduction of zikv estimated to occur between may and december , consistent with the confederations cup event, but predating the first reported cases in french polynesia. although these findings are of great value and importance to public health organizations, the authors drew an additional, and similarly valuable conclusion-large-scale patterns in human (and mosquito) mobility extending beyond air traffic data will provide more useful and testable hypotheses about disease emergence and spread than ad hoc hypotheses focused on specific events. this conclusion further supports the proposal for greater availability of epidemiological data among the scientific community. understanding both the rapid spread of the virus throughout south and central america and the caribbean as well as the initial emergence of the virus from the ugandan zika forest in the early s is important for application to the control of future outbreaks, but increasing data may not be the only answer. moreover, several different risk factors are likely responsible for these two migration events. therefore, a more comprehensive approach that allows for the analysis of multiple potential factors and their distinct contribution to independent migration events without the loss of information (i.e., use of data that span the entire evolutionary history) is imperative for fully understanding a global epidemic from beginning to present. a combined approach to understanding the emergence and expansion of an epidemiologically diverse viral population: hiv crf _ag in the congo river basin although viral spread is often attributed to human mobility [ ] , factors such as population growth and accessibility can also play an important role, as with the emergence of human immunodeficiency virus type (hiv- ) group m subtypes a and d in east africa [ ] and circulating recombinant form (crf) _ag in regions of the congo river basin (crb) [ ] . the democratic republic of congo (drc) has been reported to be the source of hiv- group m diversity [ ] [ ] [ ] ; however, the epidemiological heterogeneity of crf _ag within surrounding regions comprising the crb had remained a mystery since its discovery in [ ] , with prevalence ranging from virtual non-existence [ ] [ ] [ ] [ ] [ ] [ ] to accounting for as high as % of infections [ ] , depending on the geographical location. the region with the highest proportion of crf _ag infections, cameroon [ , ] , has been characterized by a rapidly growing infected population ( . % in to % in [ ] ), of which the majority ( %) is caused by this clade. using both molecular sequence data and unaids surveillance data [ ] , the spatiotemporal origin of crf _ag was estimated to occur in the drc in the early s ( ) ( ) ( ) ( ) , with the rapid viral population growth in cameroon following a chance exportation event out of drc. although similar phylodynamic techniques as described above for other viral species were used to infer the spatial origins of crf _ag, the timing of the origin of this viral clade was inferred using both coalescent analysis of molecular sequence data and prevalence information [ , ] . coalescent models allow for estimation of the effective population size (ne), of fundamental importance to infectious disease epidemiology, as it describes the level of genetic diversity within a population over the course of its evolutionary history. during the exponential growth period of an epidemic, the change in ne has been shown to linearly correlate with prevalence of infection [ , ] and can, therefore, be used to estimate the latter, as mentioned above, but also, when combined, faria et al. [ ] were able to show that fitting of ne and prior prevalence data can narrow the uncertainty of the temporal origin estimates by over % as compared to coalescent estimates alone. furthermore, surveillance data was recently used during simultaneous phylodynamic coalescent estimation to identify factors associated with ne dynamics throughout the entire evolutionary history of the cameroonian sequences [ ] , revealing that changes in ne were more reflective of incidence dynamics rather than prevalence, consistent with previous mathematical modeling [ , ] . although associations between ne and potentially related factors are frequently assessed, statistical analysis of these has until recently been primarily limited to post hoc examination (e.g., [ , ] ), which ignores uncertainty in demographic reconstruction, as discussed above. simultaneous implementation of evolutionary reconstruction and estimation of the relationship of covariate data with ne will be available in the newest version of beast v [ ] . although this tool has obvious implications for global assessment of factors contributing to the growth and dynamics of an epidemic, similar applications of this method to other data sets has suggested that reduced molecular data relative to covariate data may result in an impact of inclusion of the data on ne estimates. this finding posits a potential concern for convenience sequence sampling, as factors that are not responsible but are represented by large amounts of data may influence ne estimates, resulting in unreliable population dynamic inferences. as mentioned above, care is needed to ensure sufficient sampling and an appropriate sampling strategy for reliable reconstruction of the evolutionary and epidemiological history of the infectious organism of interest. traditional phylodynamic analysis applied to nosocomial outbreaks has been successfully used in the past to identify the likely source; however, the inclusion of extensive patient data, such as treatment regimens, admission and discharge dates, and length of stay, can improve not only phylogenetic estimates but also the translation of the interpretation to public health policy. epidemiological and genomic data on methicillin-resistant staphylococcus aureus (mrsa) infections were recently utilized by azarian and colleagues to reconstruct mrsa transmission and to estimate possible community and hospital acquisitions [ ] . findings from this study revealed that as high as % of the mrsa colonization within the hospital's neonatal intensive care unit (nicu) was acquired within the nicu itself. these findings indicated that current, standard prevention efforts were insufficient in preventing an outbreak, calling for the improvement of current care or alternative implementation strategies. the earlier uses of phylodynamic methods focused primarily on the molecular evolution of rapidly evolving viruses, greatly advancing the fields of virus vaccine and treatment strategies [ ] . on the other hand, epidemiological approaches have focused on influential factors related to social, economic, and behavioral patterns. integrating the phylodynamics and epidemiology approaches into a single analytical framework, referred to as evolutionary epidemiology [ , ] , represents one of the most powerful multi-disciplinary platforms. examples discussed herein of the adoption of an integrative and multifactorial mindset reveal the potential for accelerating our understanding of the emergence and spread of global infectious diseases, presently expanded to include bacterial and other cell-based pathogens. however, although a highly evolved analytical platform and an improved understanding of the translation of molecular evolutionary patterns to infection and transmission dynamics have aided in facilitating this transition, several challenges still remain. the st century has witnessed a major shift in breadth of scientific knowledge at the level of the individual researcher, requiring more focused training (e.g., molecular mechanisms) and greater collaborative efforts; meanwhile, a consensus of commonality and crossdisciplinary understanding is necessary for globalization of not only the economy, but also public health. this kind of understanding can be better achieved through interdisciplinary instruction on the theoretical and application skills related to both phylogenetics and epidemiology during early education. if successfully achieved, this combined training, in addition to access to modern ngs technology, such as handheld sequencers, would increase the mobility of labs and researchers, expanding the concept of lab-based research. mobilized labs would, in turn, reduce our current reliance on few major public health organizations and the impact of limited resources on sampling and surveillance in developing countries. increasing mobility is nevertheless inconsequential without the cooperative sharing of genomic and epidemiological information. although data are typically readily available to the public following peer-reviewed publication, the median review time of manuscripts submitted to, for example, nature is days [ ] , this in addition to the time required for thorough analysis of the original data. this timeline seems quite long in retrospect of the "spanish flu," which spread to one-third of the global population in a relatively brief -month period [ ] . data sharing prior to publication, even if only among a proportion of consenting institutions, may accelerate the process of dissemination of research findings to public health decision makers and practitioners, and its practice is not entirely unheard of. an excellent example of this type of collaboration is the "nextstrain" project (http://www.next strain.org/). nextstrain is a publicly available repository currently comprised of evolutionary datasets for ebola, zika, and avian and seasonal influenza viruses contributed by research groups from all over the world for the purpose of real-time tracking of viral epidemics. similar projects have also recently developed in other research fields. modeled after the stand up to cancer initiative, the synodos collaborative funded by the children's tumor foundation in partnership with sage bionetworks brings together a consortium of multidisciplinary researchers, who have agreed to the sharing of data and relevant information, as well as results [ ] . the ultimate goal of this cooperation is to accelerate the drug discovery process, which is highly applicable to global infectious disease research. without a similar collaborative approach to synodos, the preparedness of the global reaction to rising epidemics is at risk. recent years have been marked by local outbreaks across vast geographical regions within a timespan of months to years. hence, both the rapid dissemination of data and results and the rapid response of government and public health organizations are required for the effective prevention of a global epidemic, or pandemic. additionally, with the type of results, particularly risk factors, that are generated using this multifaceted approach (e.g., both human population and pathogen molecular characteristics), the question then arises of how organizations will actually utilize this information for treatment and prevention strategies. moreover, as the techniques and methods advance, are the infrastructures in place for global cooperation and immediate response following the presentation of a potentially more complex story? although gaps remain in current evolutionary modeling capabilities when used with epidemiological surveillance data, it is only a matter of time before the challenges described herein and elsewhere are met with more realistic models that capture the complexity of infectious disease transmission. furthermore, theoretical research in the field of infectious disease phylodynamics is still growing. consequently, there is a need for a review of the more recently developed methods and techniques and their performance, as well as their application in areas within and outside the realm of infectious disease. for example, in the era of global health, translational genomics, and personalized medicine, the accumulating availability of genetic and clinical data provides the unique opportunity to apply this approach to studies of, e.g., tumor metastasis and chronic infections, which comprise complex transmission dynamics among tissues and/or cell types, not unlike the geographical spread of infectious diseases. globalization and health understanding the development and perception of global health for more effective student education globalization of infectious diseases: the impact of migration the ecology of climate change and infectious diseases global climate change and emerging infectious diseases deciphering emerging zika and dengue viral epidemics: implications for global maternal-child health burden traditional and syndromic surveillance of infectious diseases 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prevalence of diverse hiv- strains was stable in cameroonian blood donors from two independent epidemics of hiv in maryland world health organization. who | epidemiological fact sheets on hiv and aids epidemic dynamics revealed in dengue evolution viral phylodynamics and the search for an 'effective number of infections' understanding past population dynamics: bayesian coalescent-based modeling with covariates a high-resolution genetic signature of demographic and spatial expansion in epizootic rabies virus genomic epidemiology of methicillin-resistant staphylococcus aureus in a neonatal intensive care unit does it take too long to publish research? influenza: the mother of all pandemics children's tumor foundation announces historic new initiative in neurofibromatosis research the "virogenesis" project receives funding from the european union's horizon research and innovation program under grant agreement no. . not applicable.availability of data and materials not applicable. authors' contributions bdr and cm contributed to the writing of the manuscript and creating of figures and additional material. bdr, cm, xc, mc, ms, jm, and mp discussed the contents of the manuscript and contributed to editing and revision. all authors read and approved the final manuscript. no financial or non-financial competing interest existed for any one author during the writing of this manuscript. not applicable. reported studies do not involve human participants, human data or human tissue. submit your next manuscript to biomed central and we will help you at every step: key: cord- -w uyy authors: iversen, jenny; sabin, keith; chang, judy; morgan thomas, ruth; prestage, garrett; strathdee, steffanie a; maher, lisa title: covid‐ , hiv and key populations: cross‐cutting issues and the need for population‐specific responses date: - - journal: j int aids soc doi: . /jia . sha: doc_id: cord_uid: w uyy introduction: key populations at elevated risk to contract or transmit hiv may also be at higher risk of covid‐ complications and adverse outcomes associated with public health prevention measures. however, the conditions faced by specific populations vary according to social, structural and environmental factors, including stigma and discrimination, criminalization, social and economic safety nets and the local epidemiology of hiv and covid‐ , which determine risk of exposure and vulnerability to adverse health outcomes, as well as the ability to comply with measures such as physical distancing. this commentary identifies common vulnerabilities and cross‐cutting themes in terms of the impacts of covid‐ on key populations before addressing issues and concerns specific to particular populations. discussion: cross‐cutting themes include direct impacts such as disrupted access to essential medicines, commodities and services such as anti‐retroviral treatment, hiv pre‐exposure prophylaxis, opioid agonist treatment, viral load monitoring, hiv and sexually transmitted infections testing, condoms and syringes. indirect impacts include significant collateral damage arising from prevention measures which restrict human rights, increase or impose criminal penalties, and expand police powers to target vulnerable and criminalized populations. significant heterogeneity in the covid‐ pandemic, the underlying hiv epidemic and the ability of key populations to protect themselves means that people who inject drugs and sex workers face particular challenges, including indirect impacts as a result of police targeting, loss of income and sometimes both. geographical variations mean that transgender people and men who have sex with men in regions like africa and the middle east remain criminalized, as well as stigmatized and discriminated against, increasing their vulnerability to adverse outcomes in relation to covid‐ . conclusions: disruptions to both licit and illicit supply chains, loss of income and livelihoods and changes in behaviour as a result of lockdowns and physical distancing have the potential to exacerbate the impacts of the covid‐ pandemic on key populations. while these impacts will vary significantly, human‐rights approaches to covid‐ emergency laws and public health prevention measures that are population‐specific and sensitive, will be key to reducing adverse health outcomes and ensuring that no one is left behind. the rapid spread of coronavirus disease (covid- ) has induced governments worldwide to introduce preventive measures, including physical distancing, bans on public gatherings, workplace and school closures and lockdowns designed to reduce contact and suppress transmission of severe acute respiratory syndrome coronavirus (sars-cov ), the virus that causes covid- . in the absence of a vaccine or effective pharmaceutical treatments, modelling indicates the potential of non-pharmaceutical interventions to reduce covid- related demand on health systems by two-thirds and to halve deaths [ ] . people who inject drugs (pwid), sex workers, men who have sex with men (msm), transgender people, and people in prisons and closed settings, comprise key populations in the response to hiv [ ] . in , key populations and their sexual partners accounted for almost two-thirds of new hiv infections globally [ ] . older people, men, and those with medical comorbidities including chronic pulmonary disease, cardiovascular disease, cerebrovascular disease, diabetes and compromised immunity, are at higher risk of covid- complications [ ] . several risk factors for complications, including smoking and vaping drugs, are elevated among key populations [ ] . in many settings, key populations also face stigma and discrimination, criminalization, homelessness and food insecurity, which may also exacerbate vulnerability to covid- complications. however, conditions faced by key populations vary according to social, structural and environmental factors, including the underlying epidemiology of both hiv and covid- . as highlighted by sohn et al. [ ] , the concentration of covid- risk is similar to hiv, where overlapping and intersecting individual, network and structural risks influence both acquisition and transmission and vulnerability to adverse health outcomes [ ] , as well as the ability to comply with public health prevention measures. this commentary identifies common vulnerabilities and cross-cutting themes including access to prevention, treatment and care, and the need to respect health and human rights during the covid- pandemic, before addressing populationspecific issues and concerns. | discussion . | common vulnerabilities and cross-cutting themes trust and respect for human rights have long been recognized as central to effective responses to hiv. four decades of the hiv epidemic have taught us that restrictive and stigmatizing measures drive people underground, perpetuate stigma, erode trust and respect for human rights and disproportionately impact vulnerable populations [ ] . the potential for both the covid- pandemic, and the responses to it, to amplify existing inequalities underlines the need to address criminalization, stigma and discrimination, which are also structural drivers of the hiv epidemic. discriminatory law enforcement and overly restrictive lockdown orders may disproportionately impact key populations and undermine public health strategies and community trust in government [ ] with increasing reports of sex workers, pwid, msm and transgender people being fined arrested or detained for breaching covid- related restrictions [ ] . it is important to remember that the hiv epidemic is not over, with million people living with hiv (plhiv) globally and . million new infections in [ ]. covid- -induced supply chain issues may also disproportionately impact key populations reliant on access to medications such as antiretroviral treatment (art), pre-exposure prophylaxis (prep) and opioid agonist treatment (oat), as well as services such as viral load monitoring, hiv and sti testing and condom and needle syringe distribution. in july , the world health organization (who) reported that numerous countries had experienced disruptions to provision of art during the covid pandemic [ ] . clinics around the world have reduced hours, reallocated staff or closed, leaving millions of plhiv with uncertain access to treatment [ ] . south africa, with % of the world's plhiv and . of an estimated . million plhiv not virally suppressed [ ] , has the highest covid- cases in africa and ranks in the top globally for covid- deaths per , population [ ] . in addition to disruptions in access to essential medicines, commodities and health services, some key populations are at increased risk of indirect impacts arising from responses to covid- , particularly physical distancing measures. the negative consequences of these measures on general population health and well-being, such as mental health issues arising from isolation, loss of income and residential instability, will be exacerbated in vulnerable key populations who lack the resources to physically distance or who do not have access to social safety nets or the option of working from home [ ] . in low-income countries characterized by a high burden of infectious diseases, including tuberculosis, cholera, typhoid, malaria and hiv/aids, structural and environmental conditions which impede adherence to physical distancing and hygiene measures will differentially impact key populations [ ] . unaids has cautioned against the use of covid- emergency powers or public health justifications to restrict human rights and expand police powers to target vulnerable and criminalized groups [ , ] and the united nations office of the high commissioner for human rights (ohchr) has expressed concerns about the use of imprisonment for noncompliance with public health measures [ ] . there is a need for independent mechanisms to oversee the use of police powers and to ensure that police are accountable for their actions during the pandemic. to safeguard against the pandemic being used to introduce or expand laws, penalties and police powers that criminalize key populations, unaids recommends that covid- emergency laws and powers are necessary, proportionate, non-arbitrary, evidence-informed and lawful, as well as time-limited and renewable only through appropriate democratic mechanisms [ ] . across all key populations, meaningful community participation by civil society will be essential to minimize the potential for collateral damage, maintain momentum towards global hiv targets and to ensure that the covid- response, or "cure, " is not worse than the disease itself. global networks, including the international network of people who use drugs (inpud), the global network of sex work projects (nswp), the global network of people living with hiv (gnp+) and mpact global action for gay men's health and rights have issued statements calling for urgent action to protect their communities and to address population-specific needs for prevention, care and treatment [ , - ]. challenges faced by key populations and how networks and communities are responding vary; below we highlight some of these considerations and contexts in order to illustrate the heterogeneity of the covid- pandemic and its impacts. compared to the general population, pwid have a high burden of comorbid medical conditions [ ] , exacerbated by criminalization and socio-economic disadvantage [ ] , which place them at greater risk of infection and complications. restrictions on access to key services for pwid have the potential to increase overdose deaths and hiv and hcv transmission, undermining gains made by global elimination efforts [ ] . these services, including needle syringe programs (nsp) and oat, have historically required frequent attendance and restricted access to takeaway oat [ ] . covid- travel bans and border closures are also impacting illicit markets, with shortages of precursor chemicals, declining availability of opioids and increasing prices in some settings [ ] potentially increasing demand for oat and naloxone [ ] . countries such as nepal and morocco, with moderate hiv prevalence among pwid at to % and limited covid- epidemics with less than one death per , population [ ] , have responded by working to ensure supplies of oat for multimonth dispensing (mmd) and providing unsupervised dosing. canada, a country with % hiv prevalence among pwid, and a severe covid- epidemic with . deaths per , population [ ] , has introduced biometric vending machines that dispense prescribed supplies of hydromorphone tablets to registered patients [ ] . as government services have closed or reduced their hours, drug users and peer-run services, have stepped up to maintain and provide harm reduction services to pwid, as well as distributing oat, art and hcv medications to those in lockdown [ ] . modifications have also been made to harm reduction programmes, including the distribution of supplies through outreach, pharmacies, vending machines and post and services previously rejected or under-scaled by policy makers, such as take-home dosing of methadone or hydromorphone. while policy changes to accommodate unsupervised oat demonstrate not only that flexibility in oat delivery is possible and can be done safely and effectively, oat continues to be unavailable in many settings including bahrain, belarus, brazil, cameroon, egypt, nigeria and russia [ ]. in many settings sex workers remain vulnerable to hiv and other sexually transmitted infections (sti) due to multiple factors including criminalization, challenges negotiating consistent condom use, unsafe working environments, stigmatization, discrimination and violence [ , ] . global covid- induced bans on sex work, including closures of brothels, mean that sex workers have faced loss of income and are unable to provide for themselves and their families [ ] . furthermore, reduced numbers of clients and school closures may disproportionately impact women with responsibility for school-aged children. in most countries, national social protection schemes and emergency protection measures put in place for workers exclude sex workers, particularly where sex work is criminalized. this exclusion means that many sex workers are faced with putting their safety, health and lives at increased risk in order to survive. sex worker organizations have responded rapidly by providing resources, including getting started in online/non-contact work, working safely during the covid- pandemic and dealing with stress and emotional impacts, as well as implementing income support programmes. bangladesh, where hiv prevalence among sex workers is low at . % and covid- related deaths are also low at less than one per population [ ] , is one of the few countries that has provided emergency income support for sex workers. in the absence of income support, sex work may be driven further underground with significant health and safety risks [ ] . migrant sex workers and those who use drugs may be particularly vulnerable to exploitation by clients, including unsafe work practices and lower prices. sex workers have been targeted by police for physical distancing offences in several countries and covid- -related policing of public health, including punitive crackdowns, raiding of homes, compulsory testing, arrests and threatened deportations of migrant sex workers [ ], has the potential to undermine access to health services, as well as sex workers' ability to report crimes against them. social connectedness has been shown to promote health seeking and risk reduction, including access to hiv treatment and hiv prep among gay and bisexual men (gbm) [ ] . lockdowns and physical distancing also threaten to undermine the centrality of peer support to optimizing health outcomes in this population. however, early research suggests that some gbm in high-income countries have adapted their sexual behaviour [ ] . in australia where hiv prevalence in this population is % and covid- transmission has been limited to date, gbm dramatically reduced their sexual contacts following the introduction of physical distancing restrictions [ ] . for many in the lesbian, gay, bisexual, transgender and intersex (lgbti) community, the family home may not be a safe place. in uganda where hiv prevalence among gbm is estimated at %, a raid on an lgbti community shelter resulted in people arrested and detained without access to bail, legal representation or medication for allegedly violating physical distancing measures [ , ] . their release was eventually secured after significant efforts by civil society and a court later awarded compensation for rights violations [ ] . on any given day, < million people, including pre-trial detainees, are incarcerated worldwide, with an estimated . % living with hiv, . % with hcv, . % with chronic hbv and . % with active tuberculosis (tb) [ ] , in conditions where physical distancing is impossible. many more are detained in compulsory drug detention, asylum seeker and immigration detention, and private drug treatment centres [ ] . in the us, covid- outbreaks have been reported in prisons and jails, including in new york, illinois and ohio, with both staff and detainees infected [ , ] . interim guidance by the united nations ohchr and the who has urged governments to reduce the number of people in detention by finding ways to release those at increased risk of covid- , including older detainees and people with underlying health conditions, as well as children and those with low risk profiles and people incarcerated for minor offences [ ]. estimates of the size of the transgender population vary by location, however population-based surveys report . % to . % of adults identify with a gender different to their sex assigned at birth [ ] . similarly, hiv prevalence estimates among transgender populations are highly variable within and across geographic locations, although evidence suggests transgender populations are disproportionately impacted by hiv [ ] . in some latin american countries, where hiv prevalence among transgender feminine people is typically > % [ ] , governments implemented gender-based lockdown policies, with designated days residents were permitted to leave the home based on their gender. these policies led to reports of discrimination and violence against transgender people who were away from home on a day that corresponded to their gender identity but did not match the gender listed on their identification documents [ ] . in many settings, disruptions to both licit and illicit supply chains, loss of livelihoods, changes in behaviour as a result of lockdowns and physical distancing and discriminatory and coercive policing have the potential to inflict more damage on vulnerable communities than sars-cov . unaids and who have called for a "people-centred approach" to ensure access to medication is maintained throughout the covid- pandemic [ ] . expediting differentiated service delivery such as telehealth and expanded mmd for art for plhiv and oat and nsp for pwid [ ] , and the roll-out of adaptive programmes like social protection support for sex workers, are essential to ensure that covid- is not used to disregard and further disenfranchise key populations. communities are uniting to find solutions and several countries, including african and south american nations, have developed and/or implemented community-based art distribution policies to reduce demands on health systems and to encourage people to stay at home [ ] . covid- has the potential to reverse decreases in hiv, tb and viral hepatitis mortality, however, its impacts on key populations are likely to be uneven. pwid and sex workers face particular challenges in relation to physical distancing, including indirect impacts as a result of police targeting, loss of income and sometimes both. geographical variations mean that msm and transgender people in regions like africa and the middle east remain criminalized, as well as stigmatized and discriminated against, increasing their risk of adverse outcomes. while successful containment of sars-cov- in community settings also protects prisoners and detainees, this group remains vulnerable to the negative health consequences of social isolation. and under covid- pandemic conditions, plhiv in resource constrained settings with fragile health systems will be more likely than plhiv in the global north to experience art interruptions which compromise their health. research is also needed to guide public health responses. consistent with the "right to science"' [ ] , interventions to prevent, diagnose and treat covid- need to be accessible and available to all, especially key populations for whom covid- is a pandemic on top of one or more epidemics. this has been reinforced by a recent call for a people's vaccine which guarantees covid- vaccines are available free of charge to everyone, everywhere with access prioritized for front-line workers, vulnerable people and low-and middle-income countries [ ] . biomedical, socio-economic and behavioural data on the impacts of covid- on key populations are needed, including studies designed to assess how specific policy responses increase or decrease exposure to harmful consequences and to monitor the impact of changes to service delivery. existing surveillance mechanisms, with appropriate rights-based legal safeguards, must be adapted to assess the impacts of covid- on established epidemics, including hiv and viral hepatitis, in key populations [ ] . understanding the impacts of lockdowns and physical distancing measures on key populations will be critical to monitoring trends in hiv and other infections. heterogeneity in the covid- pandemic and in the ability of key populations to protect themselves from covid- and its consequences necessitates rapid development and implementation of evidence-informed interventions that address the population determinants of transmission and local risks, while remaining sensitive to differences in the needs of key populations and the synergistic impacts of structural factors on particular communities. one of the key lessons from the hiv epidemic was that prevention responses are more effective when communities are empowered with knowledge about the virus and how to mitigate risk and are involved in, or lead, the process of developing inclusive responses. greater solidarity with, more guidance from, and the meaningful involvement of, key populations who are working to fill gaps in prevention, care and treatment, information and advocacy, is required to shape the covid- response. while covid- has exposed the moral and political barriers to implementing evidencebased public health responses [ ] , the willingness to set aside ideological objections to services such as unsupervised oat in order to save lives may be short-lived. there is an urgent need for advocacy to ensure that the introduction or scale up of evidence-based interventions during covid- are sustained and integrated into routine service delivery. working together to understand how key populations experience, engage with and emerge from, covid- pandemic-induced change, developing responses that address populationspecific needs, and ensuring that no-one is left behind, will be vital to a post-covid- transition to a more sustainable, equitable and resilient society. impact of non-pharmaceutical interventions (npis) to reduce covid mortality and healthcare demand response team consolidated guidelines on hiv prevention, diagnosis, treatment and care for key populations joint united nations programme on hiv/aids (unaids) who guidance on covid- relevant to key populations know your epidemic, know your response: understanding and responding to the heterogeneity of the covid- epidemics across southeast asia global commission on hiv and the law. global commission on hiv and the law: risks, rights & health. supplement in the time of covid- : civil society statement on covid- and people who use drugs what we know about hiv and covid- sars-cov- pandemic expanding in sub-saharan africa: considerations for covid- in people living with hiv mortality analysis: how does mortality differ across countries the right to health must guide responses to covid- unaids condemns misuse and abuse of emergency powers to target marginalized and vulnerable populations united nations office of the high commissioner for human rights (ohchr) and who. interim guidance covid- : focus on persons deprived of their liberty hiv and the criminalisation of drug use among people who inject drugs: a systematic review global burden of hiv, viral hepatitis, and tuberculosis among prisoners and detainees association between rapid utilisation of direct hepatitis c antivirals and decline in the prevalence of viremia among people who inject drugs in australia dwindling drug supply on dtes drives prices up, leaves users desperate as covid- closes border challenges in maintaining treatment services for people who use drugs during the covid- pandemic international network of people who use drugs (inpud). inpud online survey on covid- & people who use drugs (pwud): data report the global response and unmet actions for hiv and sex workers a systematic review of the correlates of violence against sex workers conflicting rights: how the prohibition of human trafficking and sexual exploitation infringes the right to health of female sex workers in phnom penh, cambodia. health and human rights mental health, drug use and sexual risk behavior among gay and bisexual men? characterizing the impact of covid- on men who have sex with men across the united states in april physical distancing due to covid- disrupts sexual behaviors among gay and bisexual men in australia: implications for trends in hiv and other sexually transmissible infections covid- in prisons and jails in the united states covid- in correctional and detention facilities -united states global epidemiology of hiv infection and related syndemics affecting transgender people strategies for engaging transgender populations in hiv prevention and care the time is now: expedited hiv differentiated service delivery during the covid- pandemic science and economic, social and cultural rights art. . .b, . , . and . [cited preventing hiv outbreaks among people who inject drugs in the united states key: cord- -hm pepp authors: nathanson, n. title: virus perpetuation in populations: biological variables that determine persistence or eradication date: journal: infectious diseases from nature: mechanisms of viral emergence and persistence doi: . / - - - _ sha: doc_id: cord_uid: hm pepp in this review, i use the term “perpetuation” for persistence of a virus in a population, since this is a different phenomenon from persistence of a virus in an infected host. important variables that influence perpetuation differ in small (< , individuals) and large (> , ) populations: in small populations, two important variables are persistence in individuals, and turnover of the population, while in large populations important variables are transmissibility, generation time, and seasonality. in small populations, viruses such as poliovirus that cause acute infections cannot readily be perpetuated, in contrast to viruses such as hepatitis b virus, that cause persistent infections. however, small animal populations can turnover significantly each year, permitting the perpetuation of some viruses that cause acute infections. large populations of humans are necessary for the perpetuation of acute viruses; for instance, measles required a population of , for perpetuation in the pre-measles vaccine era. furthermore, if an acute virus, such as poliovirus, exhibits marked seasonality in large populations, then it may disappear during the seasonal trough, even in the presence of a large number of susceptible persons. eradication is the converse of perpetuation and can be used as a definitive approach to the control of a viral disease, as in the instance of smallpox. therefore, the requirements for perpetuation have significant implications for practical public health goals. from the viewpoint of the individual host, viral infections can be conveniently divided into those that are acute and those that are persistent. however, all viruses -by definition -must be able to persist in their host population, regardless of whether they cause acute or persistent infection in individual members of that population. thus, persistence in a population is a distinct phenomenon and in this discussion i will use the term "perpetuation" to distinguish it from persistence in the individual host. once a virus has infected a defined population, it may either perpetuate indefinitely or may disappear. if disappearance is a natural occurrence, it is often described as "burn out" or "fade out", while if it is induced by human intervention, it may be described as "eradication" or "elimination". eradication represents a definitive approach to prevention of a viral disease, as in the instance of smallpox. however, to develop a strategy for eradication it is necessary first to understand the requirements for perpetuation. thus, the subject has significant implications for practical public health goals. virus persistence and perpetuation has been the subject of numerous discussions, and this presentation draws heavily on some of these publications [ , , ] . some of the biological variables that influence perpetuation are shown in table . implicit in this table is the generality that most viruses can infect a given host only once. in the instance of an acute infection, the host acquires lifelong immunity to the infecting virus and is -from an epidemiological perspectiveno longer capable of acting as a link in the chain of infection. if the virus causes persistent infection, then the outcome varies. some persistent virus infections can be transmitted as long as the host is infected (for instance hepatitis b virus and human immunodeficiency virus [hiv] ). other viruses (such as varicella zoster and herpes simplex) persist in a latent form and are infectious only during intermittent episodes of recrudescence. virus perpetuation within a human population involves a fragile equilibrium between three different categories of hosts: those who have not been infected and are susceptible; those who are actively infected and are potentially infectious; and those who have been infected and are immune. if the infection spreads too slowly within the population (transmissibility quotient, ro < ) the virus will ultimately disappear for absence of actively infected hosts. on the other hand, if the infection spreads too rapidly (ro ), the susceptible population will be "exhausted", also leading to disappearance of actively infected hosts. the size of the population under consideration is an important determinant of the dynamics of perpetuation, since the relative importance of other variables is different in smaller (< , individuals) and larger (> , ) groups (table ). in small populations, two of the most important variables are persistence in the individual host and population turnover (the rate at which new susceptible animals are introduced into the population). in large populations, variables of high importance include transmissibility, generation time, and seasonality. transmissibility (ro) is the number of new infections that are generated by each existing infection and is a property (in part) of each virus, since under a given set of conditions, some viruses will be transmitted at a much higher rate than will others. generation time is the average time between the infection of two individuals who are successive links in an infection chain; generation time may be a short as - days in the case of influenza and as long as many years in the case of hiv or hepatitis b infection. seasonality refers to the variation in transmissibility of a given virus in a specific population at different times of year. viruses that cause acute infections are often unable to perpetuate in small populations [ ] . figure shows a seroepidemiological study of poliovirus in a small eskimo village in greenland, conducted in the s. each of the three types of poliovirus had been introduced into this population. type virus had caused an outbreak of infection years prior to the study and had then disappeared; type greenland. the data show three separate introductions of types , , and poliovirus, respectively. the low frequency of type antibodies in persons ages - probably represents cross-reacting antibodies induced by infection with type virus. it appears that this acute infection "burned out" in this small (< , ) isolated population because it spread rapidly through persons who had not been previously infected and "exhausted" the susceptible population. after [ ] virus had been introduced years prior to the study date and had likewise disappeared; and type had been introduced within the prior years and (likely) had also disappeared. in such small populations, viruses that cause acute infections spread so rapidly that they quickly exhaust the susceptible population and then fade out. conversely, hepatitis b virus, which causes both acute and persistent infections can persist in small populations as shown in fig. , a study of another small eskimo population in greenland. in such populations hepatitis b virus is often transmitted during birth, from infected mothers to their newborn infants, which frequently results in persistent infections. another parameter that favors virus perpetuation is rapid turnover of the population itself. this is seen most often in animal populations some of which, in nature, may have an average lifespan of - years, so that a large fraction of the population consists of relatively young and susceptible hosts. although difficult to document in wildlife populations, this phenomenon can be more readily documented in groups of laboratory animals that are under constant surveillance. one example is a study conducted in a colony of laboratory rats that was maintained for nutritional studies [ ] . this colony was infected with rat parvovirus, a small dna virus that did not cause overt disease and was only detected by serological surveillance. rat parvovirus caused an acute infection, transmitted by the enteric route, that spread rapidly through the relatively small population of about young animals. based on the rate of spread, the virus might have been expected to exhaust all susceptibles by months of age. however, every month about % of the animals aged (persons who escaped infection as children and were infected as adults). after [ ] - months were removed to another room to be used for experiments and the same number of one-month susceptible weanling animals was introduced from a breeding colony. this continual introduction of young susceptible animals was sufficient to perpetuate an acute virus infection in a small population. as mentioned above, although a number of viruses cannot be maintained in small human populations, all human viruses are capable of perpetuation in large populations. important biological determinants of perpetuation include transmissibility, generation time, and seasonality, and these three may, in turn, determine the minimum size of the population required for perpetuation. transmissibility (ro) reflects in part the innate infectivity of a given virus, but is also determined by the density of the population, by the proportion of that population that is susceptible, and by the frequency of significant contact between different individuals within the population. the following examples illustrate the interaction of all these variables, and indicate the complexity of these relationships. measles has a special place as an example of virus perpetuation, since it is a rare instance where public health statistics can be used to monitor the ebb and flow of a specific virus infection in large human populations. measles has several attributes that -in the aggregate -are not seen for other common viral diseases: (i) there are longterm records of measles incidence, collected by many health departments in the united states and other countries; (ii) % of all measles infections manifest as illness (in contrast to % for poliomyelitis for example); (iii) the symptoms of measles are sufficiently pathognomonic so that it can be distinguished from other viral infections by clinical observers; and (iv) population-wide reports can be corrected for under-reporting (about % of measles cases were reported in most cities in the united states prior to the introduction of measles vaccine in ). exploiting these facts, bartlett [ ] published several classical studies showing that in the pre vaccine era in the united states, measles was perpetuated in cities of , or greater population but not in cities below that size. similar observations could be made in other parts of the world. for instance, in iceland, with a population of , to , , measles was introduced about times during the period to ; each time it caused an outbreak that lasted - years, and then disappeared (tauxe, unpublished, ) . although these data are striking, they remained unexplained for a number of years. why was , the limiting population size, at least in the cities included in bartlett's study? a putative explanation was put forth in several papers that focused on the seasonality of measles in temperate climates [ ] . data for baltimore (one of the cities included in bartlett's study), for the period - , are shown in fig. . absent seasonality, % of annual incidence population , measles susceptibles (estimated % of population) , annual measles incidence (estimated average) , cases in trough month ( . %) cases in trough generation period ( days) a an age profile for measles susceptibles was constructed from the age distribution reported for measles in baltimore, md, for - , supplemented with serosurveys conducted prior to the introduction of measles vaccine. the average number of annual measles infections was estimated as the size of an annual birth cohort, assuming a steady state and % cumulative attack rate for measles. cases in trough month based on data from baltimore, md, - , after [ ] would have been expected each month; however measles peaked in march at % while only . % was reported in september, the trough month. based on these observations, a hypothetical reconstruction for a city of , with . % of measles in the trough month is shown in table . in such a city, during a single trough generation period, only cases of measles would be expected. under these circumstances, it is plausible that measles infection could fade out. a further test of the hypothesis that seasonality played a critical role in the fade out of measles is provided by data from new york city and baltimore, prior to and after the introduction of measles vaccine ( table ). the data in table imply a the estimated number of susceptibles is based on the age distribution of measles cases and serosurveys of measles antibody, after [ ] that a population of about , susceptibles (data not shown indicate that about % of the total population was susceptible to measles) was required to perpetuate measles in cities of north america prior to the introduction of measles vaccine. in new york city, it can be estimated that there were about , susceptibles prior to measles vaccine and about , in the late s, after the introduction of measles vaccine. as table shows, measles was perpetuated in new york city after the introduction of the vaccine. in baltimore, vaccination was estimated to reduce the susceptible population from , to , , just below the threshold for perpetuation. in fact, measles was perpetuated in baltimore prior to measles vaccination, but showed an annual fade out each year in the late s, after the introduction of measles immunization. currently, the global effort to eradicate poliovirus is moving towards its goal. in , when who enunciated the eradication of polio as a goal, there were an estimated annual , cases of paralytic poliomyelitis worldwide; in , there were fewer than , . as we approach eradication, it is interesting to look back at the origins of this effort, the eradication of wild poliovirus in the united states in (fig. ) . amazingly, although poliomyelitis was being tracked carefully by the centers for disease control and other public health specialists, no one anticipated eradication of wild poliovirus [ ] . the explanation for this apparent paradox is not hard to find. public health surveillance was focused on poliovirus immunization surveys to determine the percent of children receiving opv, and serosurveys of immunityindicated that there was a residual susceptible population estimated at up to , , [ , , ] . it was widely assumed that this pool of susceptible hosts would continue to circulate wildtype polioviruses indefinitely, and eradication was not contemplated. under these circumstances, how could eradication occur? again, i would postulate that seasonality played a critical role in eradication [ , ] . figure shows that, as for measles, poliovirus infections were highly seasonal, particularly in the northern united states. in table , the seasonal curves are used to estimate the incidence of poliovirus infection in a hypothetical metropolitan area with a population of , , , both for the northern and the southern united states. vaccine-induced reduction of susceptible individuals in such a population can be guesstimated to reduce the number of new infections per trough generation period below the threshold for virus perpetuation. when poliomyelitis incidence data for the period through are plotted by state (fig. ) , it can be seen that each year a decreasing number of states reported paralytic polio. it can be surmised that, in area after area, the virus disappeared during the wintertime trough and was not introduced in the following summer, eventually leading to eradication. although space does not permit, it is noted a susceptible population estimates based on the age distribution of poliomyelitis and upon serosurveys of poliovirus antibodies. infections back-calculated from cases of paralytic poliomyelitis. seasonal trough based on monthly distribution of poliomyelitis cases. generation period based on studies of secondary polio cases in families. see [ ] for references that a similar phenomenon occurred with measles, but measles -with a greater transmissibility than poliovirus -was reintroduced after each fade out [ ] . the elimination of wild poliovirus in the united states gave credibility to the extension of eradication. major efforts were initiated in central and south [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , excluding imported and vaccine-associated cases. based on data in [ ] america, leading to successful eradication in the s. emboldened by these successes, who embarked on global eradication, a goal that appears within reach within the next several years. the principal residual sites where wild poliovirus continues to circulate are pakistan, india, and nigeria, and it is likely that the absence of seasonality [ , ] in these semi-tropical nations has been one of the impediments to eradication. one of the salient questions regarding the biology of hiv is: how did it emerge as a human virus? i will argue that the ability of hiv to cause persistent infections likely played a key role in its emergence, and is therefore worth a brief consideration in this essay on viral perpetuation. although circumstantial, the evidence is quite persuasive that hiv arose when a simian lentivirus, sivcpz, jumped from chimpanzees to humans [ , , ] . many animal viruses cause zoonotic infections of humans but very few of them are subsequently transmitted from person to person. most of those zoonotic viruses that are capable of limited human-to-human transmission exhibit marginal transmissibility, as evidenced by their containment using rudimentary quarantine measures and their fade out after a limited number of cycles. examples are crimean congo hemorrhagic fever virus [ ] ; arenaviruses [ ] ; ebola virus [ ] ; swine influenza virus in [ , ] ; and monkeypox virus [ ] . the sars coronavirus may be another example although to date it has not established itself as a human [ , , , ] virus, even though it underwent at least human-to-human passages in china in before being controlled by quarantine measures [ ] . rare indeed are those zoonotic viruses that become established permanently as human viruses. the best documented examples are influenza viruses, since avian influenza virus has on several occasions established itself in humans. it is noteworthy that, in several of these instances (such as the asian pandemic of and the hong kong pandemic of ) the avian virus re-assorted with a human influenza virus, to produce a genetic chimera that endowed it with novel antigenic determinants, while maintaining the capability to transmit to humans [ ] . these observations raise the questions as to how sivcpz became established as a human virus. recent studies have produced a speculative reconstruction of historical events following the hypothetical transmission of sivcpz to humans (table ) . particularly relevant to this discussion is the inference that, following transmission to humans, sivcpz was perpetuated as an unrecognized infrequent infection in rural villages in central africa during the period to [ ] . different regions of the viral genomes of sivcpz and of hiv- differ by %- % [ ] and it may be assumed that many of these changes were introduced during that -year interval. i speculate that some of these genetic changes have led to the metamorphosis of sivcpz into hiv- , to become an agent that can spread among humans with sufficient ease to be considered a virus of humans. if this is correct, then it would seem likely that the ability of sivcpz to persist lifelong in the humans that it first infected might have provided an essential window of opportunity for a virus of chimpanzees to evolve into a human virus. although tentative, these speculations offer interesting hypotheses for future research. persistent viral infections the critical community size for measles in the united states infectious diseases in primitive societies annual poliomyelitis summaries for the years - poliomyelitis summary the epidemiology of paralytic poliomyelitis in hawaii poxviruses origin of hiv- in the chimpanzee pan troglodytes troglodytes diversity consideration in hiv- vaccine selection aids as a zoonosis: scientific and public health implications the age distribution of poliomyelitis in the united states in timing the ancestor of the hiv- pandemic strains lassa fever: review of epidemiology and epizootology epidemiological aspects of poliomyelitis eradication. rev infectious dis the epidemiology of poliomyelitis: enigmas surrounding its appearance, epidemicity, and disappearance the swine flu affair. us department of health, education, and welfare, us superintendent of documents the prevalence of infection with human immunodeficiency virus over a -year period in rural zaire poliomyelitis immune status in ecologically diverse populations, in relation to virus spread, clinical incidence, and virus disappearance california encephalitis, hantavirus pulmonary syndrome, and bunyavirid hemorrhagic fevers sero-epidemiological study of rat virus infection in a closed laboratory colony filoviridae: marburg and ebola viruses poliomyelitis distribution in the united states pure politics and impure science: the swine flu affair hepatitis and hepatitis b-antigen in greenland. ii. occurrence and interrelation of hepatitis b associated surface, core, and "e" antigen-antibody systems in a highly endemic area persistent viruses molecular evolution of the sars coronavirus during the course of the sars epidemic in china epidemic of poliomyelitis in puerto rico seasonality and the requirements for perpetuation and eradication of viruses in populations recurrent outbreaks of measles, chickenpox, and mumps. ii. systematic differences in contact rates and stochastic effects author's address: n. nathanson, hagys ford rd this review draws heavily upon earlier reviews that are cited in the references, particularly yorke et al., , and nathanson and key: cord- -c xhg authors: patou, m.‐l.; chen, j.; cosson, l.; andersen, d. h.; cruaud, c.; couloux, a.; randi, e.; zhang, s.; veron, g. title: low genetic diversity in the masked palm civet paguma larvata (viverridae) date: - - journal: j zool ( ) doi: . /j. - . . .x sha: doc_id: cord_uid: c xhg the masked palm civet is distributed through south‐east asia, china and the himalayas. because of its potential role in the severe acute respiratory syndrome (sars) epidemic, it has become important to gather information on this species, and notably to provide a tool to determine the origin of farm and market animals. for this purpose, we studied the genetic variability and the phylogeographic pattern of the masked palm civet paguma larvata. first, two portions of mitochondrial genes, cytochrome b and the control region, were sequenced for a total of individuals sampled from china, the indochinese region and the sundaic region. results indicated a low genetic variability and suggested a lack of a phylogeographic structure in this species, which do not allow inferring the geographic origin of samples of unknown origin, although it is possible to distinguish individuals from china and the sundaic region. this low variation is in contrast to the well‐marked morphological differentiation between the populations in the sundaic and chinese–indochinese regions. we also used five microsatellite loci to genotype samples from two wild and four farmed populations in china, where the masked palm civet is farmed and where the sars coronavirus was isolated. these analyses also showed a reduced variability in chinese civets and showed that farmed populations did not exhibit a lower genetic diversity than wild populations, suggesting frequent introductions of wild individuals into farms. the masked palm civet paguma larvata (mammalia, carnivora, viverridae) is distributed in tropical and subtropical zones across the himalayas, china, indochina, the malay peninsula, sumatra and borneo (jennings & veron, ; fig. ) . in china, it is mainly distributed in the southern regions, but it can also be found in hubei, shaanxi, shanxi, sichuan and xizang provinces (gao, ; wang, ; smith & xie, ) . the species has been introduced to japan (corbet & hill, ) . there is no recent taxonomic revision of this species and no consensus on the validity of subspecies. based mainly on facial pattern and body colour, up to subspecies of masked palm civet have been recognized (wozencraft, ) , and up to nine in china (jiang, li & zeng, ) . although quite common in the original habitat, the masked palm civet may face a serious threat of local extinction due to habitat destruction and hunting (sodhi et al., ; steinmetz, chutipong & seuaturien, ) . in robertson & hunter, ) , it is vital to develop a tool to identify their geographic origin. although the sars-like cov has now been discovered in horseshoe bats as well (li et al., a,b) , song et al. ( ) have described the role played by masked palm civets as intermediate hosts during the / outbreak in guangdong. however, the origin of this virus is still debated (see li et al., a,b; janies et al., ) . the purpose of the present study was to evaluate the genetic diversity in the masked palm civet and to provide a phylogeographic pattern in order to determine the geographic origin of farm and market civets. this may allow for future comparisons of the species' population structure with the occurrence of the virus in its population. for this purpose, we sequenced a portion of two mitochondrial genes, the cytochrome b (cytb) and the control region (cr), both shown to be suitable markers for carnivore species phylogeography (e.g. li et al., a,b; marmi et al., ; cosson et al., ; veron et al., ) , and analysed five polymorphic microsatellite markers in chinese wild and farmed populations. for the mitochondrial study, hair and tissue samples (see table ) were obtained from different parts of the range of the masked palm civet, from various sources (see acknowledgments) or collected by the authors. two individuals of common palm civet paradoxurus hermaphroditus were used as an outgroup according to patou et al. ( ) . for the microsatellite study, the sampling was expanded to individuals from china only. they were sampled from two wild and four farm populations, as follows: one wild population from the south-east of sichuan province north-west of the liangshan mountain range (from xihua university museum) (n = ); one wild population from houhe national nature reserve in hubei (n = ); four farm populations: nibin farm in sichuan province (n = ); wufeng farm in hubei province (n = ); quwo farm in shanxi province (n= ); rongxian farm in guangxi province (n = ). natural distribution of the masked palm civet paguma larvata, in grey. molecular sampling is denoted on this map by the circles (whose size is proportional to the sampling's size). the colour of circles indicates the different genetic groups retrieved. the extraction and pcr procedures are the same as those described in cosson et al. ( ) . the end of cytb (c. bp) and the cr from the end down to the second variable domain (c. bp) were amplified using the following primers for amplification and sequencing: l : -cga agcataatattccgac- , h : -acatactggg caagcacag- (this study), lcr and hcr (cosson et al., ) ; l : -taatcgctagtccccatgaa- , h : -ctgcgtcgagacctttacg- , lcr : -gt acctcttctcgctccggg- , hsc : -ttgtttgtg gggtttggcaaga- , l : -catgtagctggact tattct- and h : -gttcatatttcaccatggg gttaac- (this study). the fragments amplified using these primers pairs overlap for about bp, allowing for appropriate assembling of the cr sequence. pcr products were visualized in a . % agarose gel to check for expected size of fragments and specific amplification. positive pcr products were purified using the 'qiaquick pcr purification kit' (qiagen, holden, germany). both strands (light and heavy) were sequenced in all cases using an automated dna sequencer (abi , applied biosystems, foster city, ca, usa). sequences were treated using sequencher . (gene codes corporation, ann harbor, mi, usa) and then the blastn . . program (altschul et al., ) to check for contamination. sequences were aligned in bioedit (hall, ) . five polymorphic microsatellite markers were isolated and characterized (see chen et al., ) , and were used for screening the two wild populations and four farm populations in china. for genotyping of the samples, pcr products were electrophoresed using an abi dna sequencer. the fragment length of the pcr products was determined with genescan (version . , applied biosystems), and marker genotypes were assigned to the animals using genotyper (version . , applied biosystems). phylogenetic analyses were performed using bayesian inference (bi). parameters were set according to mrmodeltest . (nylander, ) . bi analyses were performed with mrbayes version . (ronquist & huelsenbeck, ) using generations and five metropolis-coupled markov chains monte carlo (mcmcmc) with nodal support assessed by bayesian posterior probabilities (bpp). the burn-in period was chosen after having explored output parameters with tracer v . (rambaut & drummond, ) . analyses were run twice to ensure convergence of the results. we used the arlequin . software (excoffier, laval & schneider, ) to carry out several analyses: ( ) analysis of molecular variance (amova, excoffier, smouse & quattro, ) to test for genetic differentiation between putative geographical regions and ( ) computation of haplotypic as well as nucleotidic diversity (p) for each of the groups. in the absence of clear partitions retrieved by the phylogenetic analyses, amova were performed for different putative geographical partitions to see which could better describe our data that is find the partition that minimizes the intra-population variability and maximizes the inter-population variability. several geographical partitions were tested: ( ) group : 'china' versus group : 'indochinese region and allies'+'sundaic region'; ( ) group : 'china'+ 'sundaic region' versus group : 'indochinese region and allies'; ( ) group : 'china'+'indochinese region and allies' versus group : 'sundaic region'. as two chinese haplogroups were suggested, partitions were also attempted with these two distinct groups but this did not improve the description of our data significantly. specimens from japan (c- ; ml- ; ml- ; ml- ), hong kong (ml- ) and taiwan (l- ; l- ; l- ) were included in the same group as vietnamese samples (c- ; l- ; c- ; l- ) as they share their haplotype. a mismatch distribution of the pairwise differences among haplotypes was produced to test for the hypothesis of a sudden population expansion. genetic distances among samples were computed using mega v . (kumar, tamura & nei, ) under the kimura two parameters (k p) model. the software tcs (clement, posada & crandall, ) was used to reconstruct a haplotype network using the statistical parsimony method with a % confidence interval and gaps were treated as missing data. some ambiguities (loops) were observed in the network. they were resolved using an empirical criterion derived from the coalescent theory that is the frequency, topological and geographical criteria identified by pfenninger & posada ( ) . allele frequencies, the mean number of alleles per locus, observed heterozygosity (h o ) and expected heterozygosity (h e ) were computed using the genetix software package (belkhir et al., ) . comparison of alleles' number between different sample sizes and measurement of the allelic richness (i.e. number of alleles independent of sample size) were performed using the program fstat v . . (goudet, ) . a hardy-weinberg (hw) test for each locus in each population and global tests for all populations were performed with genepop (raymond & rousset, ) . the program fstat was also used to test for linkage disequilibrium (ld) between the polymorphic loci within each species and calculate two different measures of the genetic differentiation over subpopulations (f st , kimura & crow, ; r st , kimura & ohta, ) as well as inbreeding coefficients (f is ). the sequential bonferroni correction was applied to derive significance levels for the analysis involving multiple comparisons (rice & gaines, ) . the genetic divergence between each pair of six palm civet populations based on allele frequencies was calculated according to nei's d a genetic distance (nei, tajima & tateno, ) using population v . . (http://www.cnrs-gif.fr). genetic distances; trees were also constructed from these genetic distances values using the neighbour-joining clustering (saitou & nei, ) . bootstrap re-sampling (n = ) was performed to assess the robustness of dendrogram topologies. we also used a clustering method that does not use a spatial prior, as implemented in structure . (pritchard, stephens & donnelly, ) , to detect the maximum number of populations (k), five independent runs of k= - were performed with  mcmc repeats and a burn-in of  . k was identified using the maximal values of ln p (d) (the posterior probability of the data for a given k). moreover, the program bottleneck v . . was used to test for heterozygosity excess and to determine whether allele distributions within populations had been affected by recent changes in the size of the two wild populations (cornuet & luikart, ; luikart & cornuet, ) . we gathered portions of cytb and cr sequences for specimens of pag. larvata (genbank accession numbers eu -eu ; table ). for a few samples, we were unable to obtain the complete sequence owing to the dna's quality. the end of the cr was composed of highly repeated dinucleotidic motifs (ca), whose number differed for each individual and was excluded from the analyses. we thus used a composite fragment located at and positions (plus a short fragment between these two boundaries) of the javan mongoose complete mitochondrial genome (herpestes javanicus ay , penny & mclenachan, ) corresponding to the end region of the cytb (c. bp), the first hyper-variable region (hvr ) and the central conserved domain of the cr. these parts of the cr did not give any alignment problems and were thus aligned by eye. the dataset included characters and parsimonyinformative sites. the consensus tree provided in bi (model: hky+i+g including two substitutions' categories and a burn-in period fixed at generations) yielded a polytomy with few supported clades (fig. ) . the monophyly of pag. larvata was strongly supported (bpp = . ), and a few clades were well supported: ( ) among the three partitions tested for amovas, partition ( ) (china vs. the remaining regions) was the one that maximized the percentage of variation (c. . %), explained by differences among groups while within-population variations still explained c. % of the total variation. these results suggested that the chinese group was the most differentiated group among the three. this was also reflected by the pairwise f st (f st china/sundaic = . ; f st china/ indochina = . ; f st sundaic/indochina = . ). each of the three groups exhibited almost the same genetic characteristics (table ) . genetic distances ranged from to . % within the species, with a mean pairwise genetic distance of . %. the mismatch distribution, including all specimens (fig. ) , yielded a unimodal distribution corresponding to the expected distribution in case of a rapid population expansion. the individuals corresponded to haplotypes differing from to mutations (see fig. for the geographical distribution of these haplotypes). the haplotype network (fig. ) was rooted by haplotype l- (sichuan province). individuals from the sundaic region were all connected to this haplotype, exhibiting a star-like structure. one of the sundaic individuals (l- , singapore) was connected by a higher number of mutations (n = ) to the root haplotype. indochinese region and allies' (japan, hong kong and taiwan) individuals were nested within the network and were poorly differentiated from the chinese individuals. we noticed one distinct indochinese individual (l- ) from northern laos, differing from the root haplotype by four mutations. for the chinese group, no geographical structure (either between the different chinese provinces or . l hunf between the different farms) was retrieved. an important result was the fact that individuals from the sundaic region were not directly connected to the chinese haplogroups, while individuals from the indochinese region and allies were connected to both chinese and sundaic individuals. the five loci were highly polymorphic in pag. larvata with alleles observed and the allele number for each locus ranging from (pc ) to (pc ) ( table ) . allele frequency distributions showed rare (o %) of a total of alleles summed over loci, for a mean of . %. the overall f is values per locus ranged from À . (pc ) to . (pc ), showing an overall f is of . (table ) . pairwise f st values for different civet populations ranged from À . to . , and no pairwise f st value differed significantly from zero. the guangxi and hubei farms and hubei wild populations showed a high degree of genetic diversity (table ). in contrast, the lowest genetic diversity was observed in the shanxi farm population and the sichuan wild population in all measures of genetic diversity. the results of the hw equilibrium test (table ) , computed at each locus showed that of locus-population combinations deviated from the hw equilibrium (po . ) after correction for multiple tests across populations and loci. almost all the deviated cases are related to the positive f is , indicating an hw equilibrium deviation in the direction of the heterozygote deficit. significant ld was only found between loci pc and pc in the wild hubei population. the genetic distances ranged from . (hubei wild and farm populations) to . (sichuan and shanxi farm populations) ( table ). the pairwise f st ranged from À . (hubei wild and farm populations) to . (shanxi and sichuan farm populations) ( table ) . a genetic distance tree of the six civet populations (fig. ) was reconstructed and yielded three highly supported distinct lineages (bootstrap values of ): ( ) hubei wild and farm populations were grouped together; ( ) the sichuan wild population and the shanxi farm population clustered with the guangxi farm population; ( ) the sichuan farm population was separate from these two branches. however, no structure was identified in the bayesian clustering analysis (the maximal values of ln p (d) =À . for a given k= ) implemented in structure. according to the wilcoxon sign-rank test, under the infinite allele model, stepwise mutation model and two-phase model, for the two wild populations neither of the p-values approached significance of heterozygote excess at the % level. the two wild populations exhibited a normal allele frequency distribution shape. genetic tests for a population bottleneck performed on each of the two wild populations provided no significant genetic signature of populations' decline. the genetic divergence among the studied pag. larvata populations was quite low (mean pairwise genetic distance c. . %) and did not express any clear phylogeographic signal. the sequenced markers (cytb and cr) are usually variable in other carnivores (see studies by davison et al., ; cosson et al., ; tchaicka et al., ; but see pe´rez-haro et al., ) . comparatively, for a similar cr fragment (hvri, bp), the variability was lower in the masked palm civet than in closely related species: the binturong arctictis binturong (cosson et al., ) and the common palm civet par. hermaphroditus (patou et al., unpubl. data) . the genetic variability in masked palm civets was also explored in a nuclear gene (nuclear intron of the b-fibrinogen; m.-l. patou, unpubl. data) , which also showed low variability (mean pairwise genetic distance c. . %). comparable results were obtained for the complete cytb gene by j. chen (unpubl. data) and masuda et al. ( ) . moreover, the microsatellite analyses did not contradict these findings. these molecular results were in contrast with the marked morphological differences observed among the masked palm civet populations (pocock, a,b; g. veron, pers. obs.) , suggesting unlinked evolutionary mechanisms at the molecular and morphological levels in this species. in fact, the relationships between morphological and molecular evolution have long been debated (e.g. omland, ; bromham et al., ) . an empirical study on rodents (renaud, chevret & michaux, ) concluded that correlations between morphological and molecular evolution can be lost when organisms had to answer to an ecological change. in this case, morphological changes may occur rapidly (as observed in specialized taxa; e.g. semi-aquatic genet genetta piscivora, which exhibits very distinctive morphological features but small genetic distance values to other genets, gaubert et al., ) . in the masked palm civet, two main morphotypes can be distinguished and their distribution limit appears to be located in southern thailand by the study of a high number of museum specimens (n = ; from amnh, new york; bmnh, london; mcz, cambridge; mnhn, paris; usnm, washington; institute of zoology, beijing; and observation of wild and captive individuals, g. veron, pers. obs.). specimens from malaysia and indonesia do not have the black and white head pattern, but have a yellowish face, and their body colour is dark brown. specimens from the other parts of the range display the typical black and white head pattern with a conspicuous white longitudinal band on the nose, and the body colour is lighter, varying from beige, yellowish and grey to light brown. the northern morphotype seems to display much more variability in the colour and head pattern than the southern one. the head and body length of the northern and southern morphotypes does overlap, while hainan and taiwan specimens are smaller (head and body length not exceeding and cm, respectively) than specimens from other populations (head and body length up to cm). however, despite the low variability and lack of structure, in our molecular results, none of the sundaic individuals was found in the china-indochina clade, suggesting a putative population subdivision. three haplogroups of masked palm civets were suggested through our analyses: ( ) sundaland, ( ) the indochinese region, japan, hong kong and taiwan, poorly differentiated from ( ) china. the indochinese region and allies haplogroup was connected to the other two. in general, haplotypes were not highly differentiated from each other, with few missing intermediates inferred. the sundaic haplogroup exhibited a high number of haplotypes relative to the low number of samples. besides, one haplotype (l- from singapore) appeared to be quite divergent. this suggested a putative variability in this region. diverging haplotypes were also found in vietnam and northern laos (l- ). individuals from taiwan, hong kong and japan shared haplotypes with vietnamese samples. taiwan and hong kong individuals were closely related to those from vietnam, rather than to chinese civets, as could have been expected. however, taiwan and hong kong masked palm civets were not believed to have been introduced. the subspecies from taiwan, whose most striking morphological difference is the smaller size, cannot be validated from our results. in japan, although several authors suggest that the masked palm civet may be native (sasaki, ; masuda et al., ) , there are clear mentions of introductions (e.g. kuroda, ; dobson, ) . they took place in the s, but the exact date is unclear (kuroda, ; nawa, ) . civets were believed to come from taiwan or south china and brought as cage animals (kuroda, ) . in our study, except for one individual (c- ), which was only connected to the root haplotype, other samples from japan shared haplotypes with vietnam and taiwan individuals or were closely linked to them. this result could support an indochinese origin for the japanese civets. our results did not support a sundaic or a chinese origin. the poor variability exhibited by the chinese individuals as well as the shape of the mismatch distribution suggested a recent population expansion. on the other hand, wilcoxon's test did not suggest the occurrence of a bottleneck. the expansion could be a natural northern expansion during pleistocene as suggested by tong ( ) , or a more recent expansion due to human activity and notably by moving these animals for the farming and consumption purposes. civet trade is important (bell et al., ) and farming in china was conducted on a large scale. we found no museum specimens (n = ) having localities more northerly than 'n. corbet & hill ( ) mapped the distribution up to 'n in china; nowadays, the species is recorded as far north as 'n (zhang, ) . the lack of genetic variability and of structure within the chinese samples does not agree with the division of the chinese populations into nine subspecies as suggested by gao ( ) and jiang et al. ( ) , and, in fact, the morphological evidence does not support this subdivision either. our microsatellite analysis results suggested a reduced population subdivision across the six chinese populations studied. the mean f st value of . from all loci indicated that . % of the genetic variation was explained by the differences among individuals and . % by the differentiation among populations. the greatest genetic differentiation occurred between shanxi and sichuan farm populations (f st = . ), which indicated that perhaps they originated from two distinct populations. the lowest genetic differentiation occurred between hubei wild and farm populations (f st =À . ), which was consistent with the fact that all individuals in hubei farm were cultured many years ago from the hubei wild population. there was also reduced differentiation between the hubei and the sichuan wild populations (f st = . ). we are uncertain whether this value was an accurate measure of the level of genetic differentiation between different civet subspecies. to fully address this issue, however, more rigorous investigation with a greater number of samples from different wild populations will be needed. the results of this study showed that the farm civet populations did not exhibit a lower genetic diversity than the wild populations in china. wild civet populations were an important genetic resource for farm populations. many local farms introduced different wild populations and crossbred these with local populations, which resulted in a genetic exchange between different populations. whether captive breeding was beneficial or harmful for native civet populations is unknown, but this practice may accelerate the crossbreeding and genetic exchange between different populations. the low genetic diversity of mitochondrial dna and the lack of a structure among the masked palm civet populations did not allow inferring the geographic origin of an animal with unknown origin. indeed, we found no molecular evidence supporting the monophyly of any particular clade matching with a peculiar farm, chinese province or geographical region, and our results did not support any subspecies subdivision. however, three main haplogroups were put forward while the individuals from malaysia and indonesia exhibited a putatively higher genetic diversity. the chinese farmed populations did not exhibit a lower genetic diversity than the chinese wild populations, and this probably resulted from bringing in new wild individuals regularly. by these captures, the wild population may be at risk. the discovery of the sars-like cov in masked palm civets in the southern china markets has led to the interdiction of the farming of this species. whether this has not been replaced by increased local trapping and wildlife traffic is unknown, but should be considered. gapped blast and psi-blast: a new generation of protein database search programs genetix . . available at animal origin of sars coronavirus: possible links with the international trade in small carnivores testing the relationship between morphological and molecular rates of change along phylogenies isolation and characterization of polymorphic microsatellite markers for the masked palm civet (paguma larvata) tcs: a computer program to estimate gene genealogies the mammals of the indomalayan region: a systematic review description and power analysis of two tests for detecting recent population bottlenecks from allele frequency data genetic diversity of captive binturongs (arctictis binturong, viverridae, carnivora): implications for conservation mitochondrial phylogeography and population history of pine martens martes martes compared with polecats mustela putorius patterns of distribution in japanese land mammals arlequin ver. . : an integrated software package for population genetics data analysis analysis of molecular variance inferred from metric distances among dna haplotypes: application to human mitochondrial dna restriction data first molecular evidence for reassessing phylogenetic affinities between genets (genetta) and the enigmatic genet-like taxa osbornictis, poiana and prionodon (carnivora, viverridae) fstat, a program to estimate and test gene diversities and fixation indices (version . . ). available at isolation and characterization of viruses related to the sars coronavirus from animals in southern china bioedit: a user-friendly biological sequence alignment editor and analysis program for windows / / nt evolution of genomes, host shifts and the geographic spread of sars-cov and related coronavirus family viverridae status of the research on masked palm civets the number of alleles that can be maintained in a finite population stepwise mutation model and distribution of allelic frequencies in a finite population mega : integrated software for molecular evolutionary genetics analysis and sequence alignment the present status of the introduced mammals in japan mitochondrial phylogeography and subspecific variation in the red panda (ailurus fulgens): implications for conservation bats are natural reservoirs of sarslike coronaviruses china council for international cooperation on environment and development (cciced) ( - empirical evaluation of a test for identifying recently bottlenecked populations from allele frequency data mitochondrial dna reveals a strong phylogeographic structure in the badger across eurasia genetic variations of the masked palm civet paguma larvata, inferred from mitochondrial cytochrome b sequences notes on paguma larvata in shizuoka prefecture accuracy of estimated phylogenetic trees from molecular data. ii. gene frequency data correlated rates of molecular and morphological evolution phylogenetic relationships of the asian palm civets (hemigalinae & paradoxurinae, viverridae, carnivora) herpestes javanicus mitochondrion, complete genome. unpublished. access to genbank on genetic variability in the complete mitochondrial control region of the eurasian otter (lutra lutra) in the iberian peninsula phylogeographic history of the land snail candidula unifasciata (helicellinae, stylommatophora): fragmentation, corridor migrations, and secondary contact the geographical races of paradoxurus and paguma found to the east of the bay of bengal the palm civets or 'toddy cats' of the genera paradoxurus and paguma inhabiting british india inference of population structure using multilocus genotype data genepop version . b. population genetics software for exact tests and ecumenicism morphological vs. molecular evolution: ecology and phylogeny both shape the mandible of rodents one-way analysis of variance with unequal variances mrbayes : bayesian phylogenetic inference under mixed models the neighbor-joining method: a new method for reconstructing phylogenetic trees the present status of mustelids and viverrids in japan a guide to the mammals of china southeast asian biodiversity: an impending disaster cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human. proc. natl. acad. sci collaborating to conserve large mammals in southeast asia conservation and economic importance of the mustelids and viverrids in china phylogeography and population history of the crab-eating fox (cerdocyon thous) mammalian faunal differentiations between north and south china during the quaternary period systematic status and biogeography of the javan and small indian mongooses (herpestidae, carnivora) a complete checklist of mammal species and subspecies in china, a taxonomic and geographic reference order carnivora. in mammal species of the world distribution of mammalian species in china we thank the following people for their contribution and/or for having kindly supplied samples: wang hanzhong (wuhan institute key: cord- -b dz lnn authors: domingo, esteban; perales, celia title: viral quasispecies date: - - journal: plos genet doi: . /journal.pgen. sha: doc_id: cord_uid: b dz lnn viral quasispecies refers to a population structure that consists of extremely large numbers of variant genomes, termed mutant spectra, mutant swarms or mutant clouds. fueled by high mutation rates, mutants arise continually, and they change in relative frequency as viral replication proceeds. the term quasispecies was adopted from a theory of the origin of life in which primitive replicons) consisted of mutant distributions, as found experimentally with present day rna viruses. the theory provided a new definition of wild type, and a conceptual framework for the interpretation of the adaptive potential of rna viruses that contrasted with classical studies based on consensus sequences. standard clonal analyses and deep sequencing methodologies have confirmed the presence of myriads of mutant genomes in viral populations, and their participation in adaptive processes. the quasispecies concept applies to any biological entity, but its impact is more evident when the genome size is limited and the mutation rate is high. this is the case of the rna viruses, ubiquitous in our biosphere, and that comprise many important pathogens. in virology, quasispecies are defined as complex distributions of closely related variant genomes subjected to genetic variation, competition and selection, and that may act as a unit of selection. despite being an integral part of their replication, high mutation rates have an upper limit compatible with inheritable information. crossing such a limit leads to rna virus extinction, a transition that is the basis of an antiviral design termed lethal mutagenesis. of its corollaries is the error threshold relationship, which marks the maximum mutation rate at which the master (or dominant) sequence can stabilize the mutant ensemble. violation of the error threshold results in loss of dominance of the master sequence and drift of the population in sequence space) [ ] [ ] [ ] [ ] . the core quasispecies concepts are described by two fundamental equations: replication with production of error copies, and the error threshold relationship (fig ) . they capture two major features of rna viruses at the population level: the presence of a mutant spectrum, and the adverse effect of an increase of mutation rate on virus survival, each with several derivations (fig ) . the existence of a mutant spectrum was experimentally evidenced first by clonal analyses of rna bacteriophage qβ populations whose replication had been initiated by a single virus particle. individual genomes differed from the consensus sequence in an average of one to two the equations are the mathematical expression of the major concepts implied by quasispecies theory. the first equation describes the change of concentration of molecule i as a function of replication parameters, and its production from other molecules of the same ensemble. the second equation is the error threshold relationship, indicating the maximum amount of information (ʋ max ) and the maximum average error rate p max (p = -q; q is the copying fidelity) for maintenance of genetic information. terms are defined in the box on the right. below, an evolving mutant spectrum (with mutations represented as symbols on the genomes), with an invariant consensus sequence. details in [ ] . mutations per individual genome [ ] . fitness of biological clones was inferior to that of the parental, uncloned population, a difference also documented for vesicular stomatitis virus (vsv) [ ] . the replicative capacity of a population ensemble need not coincide with that of its individual components. the finding that a viral population was essentially a pool of mutants came at a time when mutations in general genetics were considered rare events, and virologists associated a viral genome with a defined nucleotide sequence, as still implied today in the contents of data banks [ ] . the cloud nature of qβ was understood as a consequence of its high mutation rate, calculated in − mutations introduced per nucleotide copied [ ] , together with tolerance of individual genomes to accept an undetermined proportion of the newly arising mutations, despite fitness costs. the error rate estimated for bacteriophage qβ has been confirmed, and is comparable to values calculated for other rna viruses [ , ] . high mutation rates and quasispecies were verified for other rna viruses based on dissection of viral populations by molecular or biological cloning, and sequence analysis of individual clones. john holland and colleagues were the first to recognize that a rapidly evolving rna world inserted in a dna-based biosphere had multiple evolutionary and medical implications [ ] [ ] [ ] . genome plasticity of rna viruses had been suspected for many decades. key early observations were variations in viral traits described by findley in the 's, the studies of granoff on transitions of plaque morphology of newcastle disease virus, or the high frequency of conversions between drug resistance and dependence in coxsackie a virus, among other studies with animal and plant viruses in the middle of the th century (for a historical overview and references, see ) . when put in the context of present day knowledge, we realize that these observations on phenotypic changes were the tip of the iceberg of an extremely complex reality of viral populations. high mutation rates and population heterogeneity characterize rna viruses, with consequences for viral pathogenesis and the control of viral disease. detailed studies on quasispecies dynamics in vivo have been performed with human immunodeficiency virus type (hiv- ) and hepatitis c virus [ ] [ ] [ ] . the first mathematical formulation of quasispecies was deterministic; it assumed steady state mutant distributions in equilibrium without perturbations derived from modifications of the environment or population size [ ] . these conditions are common in initial theoretical formulations of complex phenomena because they confer mathematical tractability. since then, several extensions of the theory to non-equilibrium conditions with stochastic components have been developed, with the aim of finding general solutions for multi-peak fitness landscapes. these objectives approximate quasispecies to the real case of rna viruses, which are compelled to deal with dramatic variations in population size and environment (reviewed in [ ] ). research on quasispecies has proceeded through several theoretical and experimental avenues that include continuing studies on evolutionary optimization and the origin of life, rna-rna interactions and replicator networks, the error threshold in variable fitness landscapes, consideration of chemical mutagenesis and proofreading mechanisms, evolution of tumor cells, bacterial populations or stem cells, chromosomal instability, drug resistance, and conformation distributions in prions (a class of proteins with conformation-dependent pathogenic potential; in this case the quasispecies is defined by a distribution of conformations) [ , ] . new inputs into experimental quasispecies research have come from deep sequencing to probe viral and cellular populations, recognition of interactions within mutant spectra, models of viral population dynamics related to disease progression and pathogen transmission, and new teachings from fidelity variants of viruses (the several theoretical, experimental and practical facets of quasispecies have been reviewed in several chapters of [ ] ). here we summarize the main aspects of quasispecies dynamics, and recent developments relevant to virus evolution and pathogenesis. the molecular basis of high error rates is the limited template-copying fidelity of rnadependent rna polymerases (rdrps) and rna-dependent dna polymerases (also termed reverse transcriptases, rts). in addition, these enzymes are defective in proofreading) [ ] because they lack a ' to ' exonuclease domain present in replicative cellular dna polymerases [ ] . also, postreplicative-repair pathways, abundant to correct genetic lesions in replicating cellular dna, appear as ineffective for double-stranded rna or rna-dna hybrids. the presence of a proofreading-repair activity in coronaviruses increases their copying accuracy in about -fold [ ] . this and other repair activities, that may act on standard rna or retroviral genomes [ ] [ ] [ ] [ ] , do not prevent the formation of mutant spectra, although their amplitude may be lower than for other rna viruses, at least in populations close to a clonal (single genome) origin. quasispecies dynamics will operate in any viral or cellular system in which due to high mutation rates (as a result of low fidelity nucleic acid polymerases or environmental alterations) mutant spectra are rapidly generated [ , [ ] [ ] [ ] [ ] [ ] . studies with different virus-host systems have established some general observations on the mechanisms of mutant generation, and implications of quasispecies dynamics [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in rna virus genetics when we speak of "a mutant" the entity we handle is a cloud of mutants in which the specific mutation to which we direct our attention is present in all (or the great majority of) individual genomes. there is no such a thing as "a" wild type or "a" mutant virus. they are always clouds of mutants. changes in the relative dominance of components of mutant spectra are particularly severe during in vivo infections, with complex dynamics of intra-host heterogeneity and variations. bioinformatic procedures have been developed to unveil the relationships among different but closely related genome types that may suggest some hierarchical order of mutation acquisition or identification of transmission clusters (examples are partition analysis of quasispecies, paq [ ] or quasispecies evolution, network-based transmission inference, quentin [ ] ). the crux of the matter regarding quasispecies implications is that at any given time, the viral population includes a reservoir not only of genotypic but also of phenotypic variants, conferring upon the population some adaptive pluripotency. accumulating laboratory and clinical evidence renders untenable that minority components of mutant spectra should be dismissed on the grounds of their being neutral. they can participate in selective processes and cannot be excluded from interpretations of virus behavior. variation universally involves point mutations and it can also include recombination (in its replicative and non-replicative modes), and genome segment reassortment [ ] . all modes of molecular variation are compatible, only restricted by the scope of mechanisms accessible to the replicative machinery, and for the need of viral genomes to remain functional. david evans and colleagues identified many recombination events associated with enterovirus replication, and only a few recombinants made their way towards continued replication [ ] . recombination can mediate adaptability and virulence [ ] . high mutation and recombination rates have led to the conceptual distinction between mechanistically unavoidable and evolutionarily relevant variation, in connection with the issue of clonal versus non-clonal nature of virus evolution (microbial evolution in general) [ , ] . only a minority of the nascent variation during replication can be successfully propagated. within limits that are set by biological constraints, each population is made of an array of variant genomes, with a total number which is commensurate with the virus population size. to infect a plant, animal or cell culture with infectious units can have very different consequences than to infect with infectious units, not only because the host defense systems may be overwhelmed by the high infectious dose, but also because the mutant repertoire that engages in adaptive explorations is larger. part of the variants of a mutant spectrum, either in isolation or in consortium with others [ ] , may perform better than other members of the same population in the event of an environmental change. selective pressures favor replication of some components of a mutant spectrum over others, despite all of them being interconnected by mutation. differential performance can be at the level of viral genomes (during replication, intracellular gene expression, interaction with host factors, etc.) or viral particles (for thermal stability, entry into or exit from cells, to withstand neutralizing antibodies, etc.) [ , [ ] [ ] [ ] , [ ] [ ] [ ] . adaptability of rna viruses is linked to parameters that facilitate exploration of sequence space: genome size ( . to kb), population size (variable but that can attain an impressive individual genomes in an infected host at a given time), replication rate, mutation rate, fecundity (yield of viral particles per cell), and number of mutations required for a phenotypic change (surprisingly low for several relevant traits) (see [ ] ). mutant spectrum dynamics has been depicted in different ways, and we have chosen one that encompasses frequent events in natural populations and research designs, such as virus isolation from an infected host, adaptation to cell culture for studies on experimental evolution, or adaptation to alternative hosts in vivo (fig ) . despite the complexity conveyed by the figure, the reality is even more complex, given the large population sizes, with an indeterminate proportion of genomes actively replicating at any given time (sometimes equated with the effective population size in general genetics), and harboring multiple mutations per genome. the scenarios suggested by current experimental data defy our imagination. the relative frequency of individual mutations fluctuates in an unceasing exploration of sequence space [ ] [ ] [ ] , with phenotypic changes (not only genotypic changes) being far more frequent than previously thought. the experimental evolution design that consists of passaging viral populations for long time periods (many sequential infections) is often extremely revealing. in foot-and- mouth disease virus (fmdv) such a design led to a remarkable phenotypic diversification into subpopulations of colonizers and competitors, that modulated virulence of the mutant ensemble [ ] . in hcv such a design unveiled continuous mutation waves and a more accurate understanding of the types of fitness landscapes occupied by high fitness viruses [ , ] . the nucleotide sequence of an individual genome from a population (no matter which the degree of population complexity might be), can be determined either following a biological or molecular cloning event or by deep sequencing of entire viral genomes, in a manner that mutation linkage (assignment of different mutations to the same genome molecule) can be established. each of these procedures implies some limitations: biological cloning can bias the representation in favor of infectious genomes, while molecular cloning can introduce noninfectious (defective) genomes in the analysis [ , , ] . whole genome quasispecies description is still technically challenging due to the artifactual introduction of mutations. most current deep sequencing platforms yield sequences of short reads for a given amplicon (sequence under analysis); minority mutations in an amplicon cannot be reliably linked to mutations in a different amplicon of the same genome; at most, statistical inferences on linkage can be proposed. despite these limitations, control experiments and improvements of bioinformatic procedures support that the majority of sequence heterogeneity analyzed in viral populations indeed reflects differences in the natural template populations. if mutation linkage can be solved on a routine basis, a new wave of molecular information relevant to epistatic interactions will enter the picture. there are additional levels of indeterminacy in the sequential analysis of viral populations, in particular those replicating in vivo. components of the mutant spectrum represented at a given time in the sample taken for sequencing may differ from those in the next time point, due either to sampling uncertainties or bona fide fluctuations of genome frequencies. it is not justified to accept a rough similarity because even a single mutation in a given sequence context may affect biological properties [ ] . in the words of john holland and colleagues: "it is important to remember that every quasispecies genome swarm in an infected individual is unique and "new" in the sense that no identical population of genomes has ever existed before and none such will ever exist again" [ ] . on top of the fleeting nature of any mutant distribution, the standard methods available for quasispecies characterization provide genomic sequences of a minority of the population (estimated in − to − for molecular cloning-sanger sequencing, and in − to − for deep sequencing; reviewed in [ ] ). we can only have an approximate representation of viral populations and their dynamics, as evidenced by many experimental studies [ , , , , , , , ] . the points summarized in previous sections fully justifies addressing analytical tools towards the mutant spectrum rather than ignoring it or considering its presence a side issue. use of consensus sequences to describe the genome of a virus isolate, despite being warranted by the difficulties of conveying the information recapitulated in a mutant spectrum, blurs and enfeebles biological interpretations. experimental results have demonstrated that minority genomes from a mutant spectrum (that cannot be identified by examining the consensus sequence) can include mutations that confer resistance to antiviral inhibitors, neutralizing antibodies or cytotoxic t cells, or that can alter the capacity to induce interferon (ifn) or to respond to ifn, virulence or particle stability, among other phenotypic traits [ , , , , [ ] [ ] [ ] [ ] [ ] . mutant spectra can also mediate cyclical adaptation to different cell types [ ] . a mutant spectrum defines a consensus but the consensus is an abstraction; it may not be represented in the population. many events in viral pathogenesis and evolution are due to mutant spectrum modifications or interactions which cannot be properly interpreted solely on the basis of consensus sequences [ , [ ] [ ] [ ] , , , , , , , , ] . mutant spectra are not mere aggregates of mutants acting independently. they are often engaged in collective responses of two major types: those that depend on the presence of sets of variants, and those that rely on intra-mutant spectrum interactions. behavior of reconstructed quasispecies. in some cases of sweeping selection (very strong selection for a trait), an individual (or a limited number of individuals) that encodes signatures prone to be selected, may approach dominance while becoming the founder of a mutant cloud (because formation of a cloud is inherent to replication). conditions for dominance (in this case in response to selection) are that the genome senses the selective sweep and that its replication in the new selective environment is permitted. in other cases, a collection of mutants is selected. this was illustrated with a fmdv quasispecies that was reconstructed in the laboratory with multiple antigenic variants (each at low frequency) that belonged to two different categories, and shared resistance to the same monoclonal antibody [ ] . one category included mutants with an amino acid substitution that affected receptor recognition (since the antigenic determinant overlapped with the integrin receptor recognition site); in the other category, the substitutions affected the antigenic determinant but not the receptor recognition site. passages of the virus in absence of the monoclonal antibody resulted in dominance of antigenic variants that maintained the receptor recognition capacity, but the dominant variants were surrounded by a cloud of mutants of the other antigenic variant category. conversely, passages in the presence of the antibody led to selection of variants with altered receptor recognition, surrounded by a cloud of antigenic variants that maintained receptor recognition. the results underlined the role of mutant clouds in selective events, and unveiled a new mechanism of antigenic flexibility [ ] . quasispecies memory. quasispecies memory is a type of molecular memory dependent on the recent history of the evolutionary lineage and the integrity of the mutant spectrum [ , ] . the search for memory was prompted by the complex adaptive system behavior of a viral quasispecies, suggested by the presence of core information (considered the one that defines viral identity) despite variation of constitutive elements (the mutant spectrum). a wellknown example is memory in the immune system that mobilizes and expands minority components in response to stimuli previously faced by the system [ ] . in the experiments designed to identify memory in viral quasispecies, members of the mutant spectrum increased in frequency as a consequence of their replication during a selection event that drove them towards dominance. when the selective constraint was withdrawn, memory genomes remained at levels that were -to -fold higher than the basal levels attributable solely to their generation by mutation, as documented with independent fmdv genetic markers, and with hiv- in vivo [ , , , ] . thus, memory is a history-dependent, collective property of the quasispecies that confers a selective advantage to respond to environmental changes previously experienced by the same evolutionary lineage. it can be manifested only if the mutant spectrum maintains its completeness, since memory is lost when the population undergoes a bottleneck event that excludes minorities. a relevant example of the consequences of memory occurs in antiviral pharmacology with the administration for a second time of the same or a related antiviral agent (capable of evoking shared resistance mutations) used in a previous treatment. the second intervention may face inhibitor-resistant memory genomes from the earlier treatment, thus contributing to virus escape [ ] . this is an aspect that has not received adequate attention in the planning of antiviral interventions for patients who fail a first treatment and have to be subjected to a second treatment. individual genomes surrounded by a cloud of related mutants can be either suppressed to be kept at low frequency, or helped to be maintained in the population. the two alternative fates are dependent on several factors, one being the surrounding mutant spectrum in those steps of the infectious cycle in which an effective competition among variants is established, for example within replication complexes. this important concept was first derived theoretically [ , ] , and then approached experimentally with several viruses. in an early study, juan carlos de la torre and john holland described suppression of high fitness vsv by mutant spectra of inferior fitness [ ] . suppressive effects have since been documented with standard and mutagenized viral populations. some examples are: • suppression of high fitness antigenic variants of fmdv by low fitness antibody-escape mutants [ ] . [ ] . • suppression of pathogenic lymphocytic choriomengitis virus (lcmv) (that cause growth hormone deficiency in mice) by non-pathogenic lcmv variants [ ] . • suppression of fmdv by a mutagenized fmdv population [ ] . • suppression of fmdv by capsid and polymerase fmdv mutants [ ] . • suppression of drug-resistant viral mutants during antiviral therapy [ , ] . opposite to suppression is maintenance of a mutant either by a favorable position in a fitness landscape or by interactions of complementation or cooperation with members of the mutant spectrum. the position in a fitness landscape influences vulnerability to mutations, as popularized with the terms "advantage of the flattest" or "survival of the flattest", indicating that a variant located at the top of a sharp fitness peak has higher probability to decrease fitness as a result of new mutations than the same variant located at a fitness plateau [ ] [ ] [ ] . survival of the flattest has been also proposed as an ingredient in some models of the error threshold [ ] . collective behavior of viruses was documented with mutant rna viruses resistant to nucleotide analogues. the study of this class of mutants has been instrumental for the understanding of the molecular basis of template copying fidelity, and the consequences of fidelity alterations in the adaptive capacity and pathogenic potential of rna viruses [ ] [ ] [ ] . in the first mutant studied, amino acid substitution g s in the pv polymerase resulted in about four-fold increase in template-copying fidelity. this modification reduced pv adaptability and infective potential in vivo [ , ] . the mutant in isolation did not replicate efficiently in the brain of susceptible mice, but it did when its mutant spectrum was broadened by -fluorouracil mutagenesis or when it was co-inoculated with wild type pv [ ] . complementation (often occurring when a functional protein encoded by a set of genomes is used by another set of genomes whose encoded protein is not functional) may underlie some collective responses of quasispecies such as fitness of individuals isolated from a population being inferior to fitness of the population [ , ] . complementation was described between two truncated fmdv genomic forms [ , ] . the genomes with internal deletions became detectable upon high multiplicity passage of a clonal population of standard fmdv, a virus with a monopartite single stranded rna genome. infectivity was generated by complementation of the two truncated forms, in absence of standard, full length fmdv genomes. for complementation to be effective, prior exploration of sequence space through point mutations was a requirement [ ] . the system underwent a remarkable evolutionary transition akin to genome segmentation. drastic genetic lesions in viral genomes are difficult to observe unless a mechanism such as complementation comes into the rescue of the deviant genomes. additional examples of complementation among rna viruses have been reported ( [ ] [ ] [ ] ; for review see [ , ] ). complementation is a means to maintain defective genomes at detectable frequencies in viral populations. a distinction has been made between complementation and cooperation, in which two different genomes give rise to a new phenotype through the interaction between two variant proteins [ ] . an example of cooperation was characterized during studies with measles virus on membrane fusion which is essential for virus entry into cells. for this virus fusion is mediated by two proteins termed h and f. a truncated h was deficient in cell fusion but the activity was regained when the truncated h was accompanied by two forms of f but not one of the forms individually [ ] . therefore, complementation, cooperation, interference and suppression can emerge from interactions among components of mutant spectra that have their origin in random mutations. selection acts on whatever sets of mutants can provide a useful trait, to turn random occurrences into biological meaning. a means to interrupt the participation of individual genomes in interactions with their mutant spectrum is for the quasispecies swarm to undergo drastic reductions in population size that isolate one or few individual genomes from their surroundings. such reductions are termed bottlenecks (fig ) , and they have an important participation in shaping evolutionary lineages for all kinds of organisms, and also for viruses. bottleneck events are also depicted in fig ( plaque-to-plaque transfers in box at the left). they occur frequently not only upon host-to host transmission but also inside infected hosts [ ] [ ] [ ] , and they can perturb positive and negative selection events in processes that are difficult to identify and characterize. drastic bottleneck events have been reproduced with laboratory populations of viruses in the form of plaque-to-plaque transfers [ , ] (depicted in fig ) . this design served to verify experimentally the operation of müller's ratchet, or fitness decrease by the irreversible incorporation of mutations in asexual organisms in absence of compensatory mechanisms [ ] . the serial bottleneck transfers unveiled the presence of rare mutations, not seen in standard laboratory or natural viral populations. in absence of forced bottleneck events, such rare mutations would be lost by negative selection because of the fitness cost they inflict [ ] . the investigation of how fmdv clones debilitated by müller's ratchet regained replicative fitness revealed several alternative molecular pathways for fitness recovery [ ] . the implications of this observation went largely unnoticed until recent results with hepatitis c virus (hcv) have also suggested the accessibility of multiple pathways for fitness gain [ , ] . also, extensive passage of a biological clone of fmdv in bhk- cells conferred the capacity to infect several human cell lines in addition to the expected fitness increase for multiplication in bhk- cells [ ] . thus, several lines of evidence suggest that fitness gain in a specific environment may paradoxically broaden the phenotypic potential of a virus. it will be interesting to investigate whether focused adaptation of other viruses to a specific environment may also entail a broadening of diversity, with many phenotypic variants attaining similar fitness levels. if generalized, this broadening of phenotypic space would provide a new interpretation of the molecular basis of adaptation, and explain why adaptation to alternative environments may not lead to attenuation. deprivation of an individual virus from possible suppression, complementation or cooperation, may represent a liberation to initiate a new evolutionary process, or a condemnation to extinction. if liberated from suppression, the isolated genome must replicate and be able to reconstruct a mutant cloud to regain adaptive capability. this has led to the suggestion that high mutation rates evolved to allow such mutant spectrum recovery following bottlenecks. other models attribute high mutation rates to adaptive optimization independent of bottlenecks, or to a mechanistic consequence of rapid replication (reviewed in [ ] ). whatever their ultimate origins, high mutation rates serve the purpose of adaptation in multiple circumstances, not only following bottlenecks. a founder virus can introduce a different phenotype for the ensuing evolution. evolution of viruses in nature and as disease agents can be viewed as succession of mutant spectrum alterations, subjected to expansions and reductions of population size in a continuous interplay of positive and negative selection and random drift. while short-term (for example, intra-host) evolution is observable and measurable, viruses may appear to be relatively static in the long term for decades (as seen with antigenic variants of fmdv [ ] ) or longer. intra-host evolution is generally more rapid than inter-host evolution, as documented with viruses [ ] and other biological systems [ ] . apparent invariance may be the result of selection for long-term survival of populations that have previously frenziedly tested evolutionary outcomes in short-term processes [ ] . soon after quasispecies was evidenced for viruses, some medical implications were made explicit [ , ] . several specific or general points (reviewed in [ , , ] , and in several chapters of [ ] ) can be succinctly exposed as follows: • high mutation rates and population heterogeneity endow viruses with the potential to escape immune pressures (including those due to vaccination) and antiviral inhibitors used in therapy. it is an open question if vaccination can promote long-term evolution of antigenic determinants. • attenuated rna virus vaccines can revert to virulent forms. rna viruses released in nature for pest control purposes can mutate to new phenotypes. • virus attenuation and virulence is dependent on viral genetic traits. variant forms of a given virus may display increased virulence or atypical disease. • components of a mutant spectrum can exhibit a different cell tropism or host range than most genomes in the same population, with implications for the emergence and re-emergence of viral disease. • viral pathogenesis is influenced by microevolutionary processes in which some viral subpopulations are replaced by others to persist or to invade new cell types, tissues or organs. • the larger the actively replicating (effective) population size and the replication rate, the most effective is exploration of sequence space for phenotypic expansions that favor survival and persistence. • there is a connection between four parameters that caracterize viruses during infection processes: replication rate (the rate at which viral rna or dna is synthesized intracellularly for viral progeny production), viral load (the total amount of virus quantified in an infected host or host compartment), genetic heterogeneity, and replicative fitness (the yield of infectious particles that can contribute to the next generation). they can influence disease progression, and any of them can be targetted for disease control. in all interactions conductive to disease, the host cells individually and as groups in tissues and organs play decisive roles. the consequences of a viral infection are always host-dependent. however, the virus itself poses a major challenge that a deeper understanding of quasispecies dynamics is helping to confront. there is an increasing perception that darwinian principles should assist in the planning of antiviral designs [ ] . the aim of vaccination is to evoke a protective response that either prevents virus replication or disease. the aim of an antiviral pharmacological intervention is to inhibit virus replication to provide the immune system with an opportunity to clear the virus. expressed simply, the direct danger for vaccination and treatment is that virus can escape through selection of mutants resistant to vaccine-triggered defense components or to the externally administered inhibitors. this has led to several proposals to confront viral disease, that can be summarized as follows (reviewed in [ ] ): vaccines should include repertoires of b cell and t cell epitopes to evoke an ample immune response. the broad response should minimize selection of escape mutants that may be present as minority components in mutant spectra, as repeatedly documented experimentally [ , , , ] . with the current types of available vaccines, those that best comply with the multiple epitope requirement are, in the order of expected efficacy to confer protection against highly variable viruses: attenuated > inactivated whole virus > several expressed proteins > one expressed protein > multiple synthetic peptide antigens > single peptide antigen. the scarcity of effective synthetic vaccines for rna viral pathogens despite huge scientific and economic efforts is a reflection of the underlying problems. antiviral monotherapy (use of a single antiviral agent) is to be avoided. the following recommendations have been made and in some cases successfully implemented: • inhibitors used in combination should target different viral gene products. • splitting a treatment into two steps: first an induction regimen, and a second maintenance regimen. drugs administered in the two steps should be different. • targetting of cellular functions needed for the virus life cycle. • use of innate immune response-stimulating drugs (for example, inhibitors of enzymes involved in pyrimidine biosynthesis). • combined use of immunotherapy and chemotherapy. • lethal mutagenesis or virus extinction by excess of mutations introduced during viral replication. these strategies (whose supportive theoretical and experimental evidence has been reviewed in [ , ] ) have as their main objective to avoid selection of treatment-escape mutants by multiple selective constraints that cannot be surmounted by the virus. control is effective either because exploration of sequence space cannot reach the required multiple mutations (even when recombination is available) or because the multiple mutations inflict a severe fitness cost [ ] . vaccines exposing multiple epitopes and combination therapies follow the same strategy whose aim is to limit possible escape routes to viral quasispecies in the face of the suppressive constraint. lethal mutagenesis is the process of virus extinction at the error rate at which a virus can no longer maintain its genetic information [ , , , , , , , ] . application of lethal mutagenesis as an antiviral strategy deserves attention in the context of the present article because its origins lie in quasispecies theory, in the form of the error threshold relationship (fig ) . both the error threshold and lethal mutagenesis are highly fitness landscape-dependent, but both can occur in complex fitness landscapes as those pertinent to viral populations [ ] . the term lethal mutagenesis was coined by lawerence loeb and colleagues [ ] , and it is now widely used to describe the antiviral activity of base and nucleoside analogues that increase the viral mutation rate. although several models have been proposed to account for virus extinction by excess mutations [ ] , an extension of the violation of the error threshold stands as a likely mechanism ( [ ] ; recent review in [ ] ). interestingly, some antiviral agents licensed for human use, initially thought to act only as inhibitors of viral replication, may actually exert their antviral activity against some rna viruses at least partially by lethal mutagenesis. this is the case of favipiravir (t- ; -fluoro- -hydroxy- -pirazinecarboxamide) and ribavirin ( -β-d-ribofuranosyl- -h- , , -triazole- -carboxamide) that are currently being intensively investigated as lethal mutagens [ ] . defense mechanisms based on genome modification of invading genetic parasites such as editing cellular activities that are recruited as part of the innate immune response (adar, apobec, rip, etc; reviewed in [ ] ) represent a natural counterpart of the principle utilized by lethal mutagenesis. applicability to pathogenic cellular elements is a real possibility, and lethal mutagenesis to control tumor cells is an active field of investigation [ , ] . thus, the recognition of quasispecies dynamics has suggested some fundamental guidelines for disease prevention and control that are gradually permeating clinical practice. this is in line with the recognized need to apply darwinian principles to the control of infectious disease. the main concepts covered in the present article and their domains of applicability are summarized in table . the adequacy of quasispecies theory (versus other formulations of evolutionary dynamics [ ] ) as a framework for the error-prone replication of viruses and its consequences stems from its including mutation as an integral part of the replication process table . summary of main concepts related to quasispecies and their implications a. implications for virology references limited template-copying fidelity leads to formation of dynamic mutant distributions. they mediate virus adaptability. [ , , , ] phenotypic reservoir mutant spectra are a phenotypic reservoir for selection to act upon [ , , ] adaptive parameters viral quasispecies adaptability relies on six parameters: genome size; population size; replication rate; mutation rate; fecundity; and number of mutations required for a phenotypic change [ , , ] mutant spectra are not mere mutant aggregates. emergent behavior can result from positive interactions of cooperation or complementation or negative interactions of interference among components cf the mutant spectrum [ , , [ ] [ ] [ ] , [ ] [ ] [ ] quasispecies memory a record of past genome dominances that prepares a viral population to respond to a selective constraint previously experienced by the same lineage. bottlenecks erase quasispecies memory. [ , , , ] the total number of genomic sequences available to a virus. adaptation is a movement towards a favorable region of sequence space. de-adaptation (i.e. lethal mutagenesis) is a movement towards unfavorable regions of sequence space. [ , , , ] population bottleneck a drastic reduction in population size. it promotes random drift in evolutionary outcomes. the diversifying effect of bottlenecks is accentuated by the cloud nature of viral populations. [ , , , ] biological constraints high mutation rates expand sequence space occupation. biological constraints impose negative selection on many newly generated mutants. constraints contribute to maintenance of virus identity. [ , , ] progress of an infection is often associated with virus adaptation to host environments. variants of the same virus can differ in disease potential (virulence). [ , , ] quasispecies and long-term evolution short-term evolutionary rate based on reorganization of mutant spectra is faster than long-term evolutionary rate. conceptual links between quasispecies and phylodynamics at the epidemiological level are needed. [ ] aconcepts are listed in the order relevant to the topics covered in the text, and serve to underline key points and some supportive studies. the concepts are expanded in the text, with additional references. [ ] . quasispecies dynamics poses a great challenge for the molecular interpretation of shortterm evolutionary events that bear on virus-host interactions and disease processes. a rewarding aspect of progress in having captured the meaning of the challenge (at least partially) is that we can exclude some of the prevention and control strategies that once were considered an option. a significant example is the historical rejection of combination therapies as contrary to the established canons of pharmacology, while now monotherapy is considered a risky practice (for discussion of this point, see [ ] ). we understand now that focused antiviral barriers that involve a single constraint (one inhibitor, one monoclonal antibody, one peptide antigen as vaccine) have a large probability of failing. likewise, attempts to produce "universal" drugs, vaccines or diagnostic tools are unlikely to succeed given the intra-population diversity (present and potential) of the pathogenic agents to be controlled. a viral genome region which is conserved among types, subtypes, isolates may be so only regarding a consensus sequence but not the underlying mutant spectrum. methods are now available to identify low level mutations that may predict escape from selective constraints. on a related note, it remains extremely unlikely to predict the emergence and re-emergence of viral diseases for a number of interconnected reasons, not the least important being pathogen adaptability [ ] . the outlined limitations to predict the occurrence of viral diseases and to control them are based on our current understanding of viral complexity and dynamic change of such complexity. obviously, we may be wrong, and in science we are open to the unexpected. quasispecies poses also a challenge for the annotation of the events we witness. reality is far more complex than the means we have developed to describe viral populations in continuous change. how could the problem we approached? procedures to organize and relate sequences for phylodynamic purposes need updating to exploit increased computing power to handle mutant spectra rather than one or few (consensus or other) sequences from each biological sample. the expanding number of sequences expected to become available including complete genomes (that will allow mutation linkage to enter the picture) if handled properly, may inform of the molecular basis of new phenotypes. the penetration into mutant spectra has also modified the concept of rare mutation since what in terms of consensus could be catalogued as rare may in fact be frequently occurring but rarely observed. a mutation which has low frequency at one time point or in a given environment may rise to high frequency at another time point or in a different environment. rare mutations that populate mutant swarms may belong to defective genomes exerting relevant host interactions [ ] . on a more general note, recognition of viral quasispecies was premonitory of the impressive diversity in the biological world that the metagenomic approaches are currently unveiling, including cellular heterogeneities whose biological implications remain largely unexplored. supporting information s text. version history of the text file. 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drug resistance. handbook of antimicrobial resistance lethal mutagenesis of hiv with mutagenic nucleoside analogs the increasing impact of lethal mutagenesis of viruses error catastrophe and antiviral strategy perspective: apobec mutagenesis in drug resistance and immune escape in hiv and cancer evolution lethal mutagenesis: targeting the mutator phenotype in cancer human cancers express mutator phenotypes: origin, consequences and targeting unifying evolutionary dynamics microbial threats to health. emergence, detection and response the defective component of viral populations evolutionary virology at we thank colleagues and students who have participated in research on viral quasispecies and its conceptual origins. we dedicate this article to the memory of manfred eigen ( eigen ( - . key: cord- - y u h y authors: ediev, d. m. title: population heterogeneity is a critical factor of the kinetics of the covid- epidemics date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: y u h y the novel coronavirus pandemic generates extensive attention in political and scholarly domains. its potentially lasting prospects, economic and social consequences call for a better understanding of its nature. the widespread expectations of large portions of the population to be infected or vaccinated before containing the covid- epidemics rely on assuming a homogeneous population. in reality, people differ in the propensity to catch the infection and spread it further. here, we incorporate population heterogeneity into the kermack-mckendrick sir compartmental model and show the cost of the pandemic may be much lower than usually assumed. we also indicate the crucial role of correctly planning lockdown interventions. we found that an efficient lockdown strategy may reduce the cost of the epidemic to as low as several percents in a heterogeneous population. that level is comparable to prevalences found in serological surveys. we expect that our study will be followed by more extensive data-driven research on epidemiological dynamics in heterogeneous populations. because of the novelty and urgency of the situation, epidemiological models inform decision-making , - in addressing the covid- pandemic. those models indicate high contagiousness of the virus and raise concerns about the majority of the population to be infected (if not vaccinated). the basic reproduction number ܴ of the pandemic at its beginning was estimated to be around , - , which implies െ ܴ ⁄ , i.e., about percent of the population must be infected or vaccinated before the infection may be controlled without lockdown measures. this conclusion has affected mitigation policies in many countries, it has also contributed to expectations of recurrent waves of the epidemic. those models, however, ignore varying social engagement, epidemic-awareness, and hygiene preparedness that, along with other factors, contribute to the varying propensity of contracting the disease and spreading it to others. various reports suggest - percent of cases may be responsible for percent of the covid- transmissions [ ] [ ] [ ] . these findings illuminate the fact that while the majority of people may barely contribute to the spread of the epidemics thanks to either limited social engagement or higher alertness and better hygiene, few others may become superspreaders infecting dozens of people. an essential practical conclusion from this conclusion was a call to aim the mitigation policies at superspreaders to reduce the basic reproduction number (average number of secondary infections per one initial infected person) and contain the spread of the infection. another aspect of the heterogeneity, however, may demand to revise that conclusion and readdress the prospects of the pandemic and mitigation policies. the population heterogeneity is an essential player in the kinetics of the epidemic, because when the minority who contributes most to the spread of the virus contracts the disease and develops immunity, the outbreak may abruptly come to an end before the expected majority gets affected. differential contagiousness also matters for how to manage the lockdown policies and whether to assume the recurrent waves of the epidemic after the lift of the social isolation measures or autumn cooling. furthermore, population heterogeneity may shorten the course of the outbreaks, because those with higher social engagement will also be the first to catch the infection. in figure is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) reproduction number of three, the epidemics could have been checked after percent of the population gets infected. in reality, that threshold may be surpassed thanks to the gained momentum of the spread of the infection. in the heterogeneous cases, the total numbers infected are also substantial ( . and . percent, respectively) but much lower than in the homogeneous case. the peak levels of the infected population are also much higher ( . percent) in the homogeneous population than in the heterogeneous ones ( . and . percent). also note that the more heterogeneous is the population, the earlier is the peak of the epidemic. an intuition to this observation is that the faster infection (and recovery) of the superspreaders accelerates the epidemics in its early phase while slowing it down in a later phase. in panes b-d, we present results for three timing options for the lockdown that lasts over days and reduces the spread of the virus by percent. when started too early (day , pane b), the lockdown leaves too many people susceptible to the virus and facilitates a substantial second wave. the total infected population is nearly the same as in the no-lockdown variant for the homogeneous population but considerably lower for the heterogeneous populations. with a better timing of the lockdown, the long-term costs of the epidemics are much lower. the lockdown presented in pane c (starts in day ) is optimal for the more heterogeneous population that experiences, with the optimal lockdown timing, no second wave (and the total number infected is minimal at . percent). that lockdown, however, is yet too early for the less heterogeneous population where a moderate second epidemic wave develops and leads to a total of . percent infected (a substantially higher cost as compared to the minimal cost of percent associated with the lockdown starting in day ). in the homogeneous case, the second wave is even higher, and almost everybody ( . percent) is, again, gets infected. only a later lockdown that starts in day (pane d) produces the optimal result for the homogeneous population ( . percent infected). while the first wave of the epidemics in the heterogeneous cases is earlier and more compressed as compared to the homogeneous case, the second wave, on the contrary, is later and more stretched out. even if beneficial in terms of a lower peak, an extended small second wave may misguide the policymaker about the long-term efficiency of the lockdown measures. heterogeneous scenarios show much lower long-term costs of the epidemics and peak levels of the infected as compared to the traditional homogeneous case. if the lockdown had been more selective, better protecting the non-spreading population, those numbers could have been even smaller. indeed, the epidemics could, in principle, be contained after most of the superspreaders were infected (bringing total infected populations down to about . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . expectations that about percent of people may be infected before containing the pandemic were implicitly based on assuming population homogeneity. contrary to those expectations, we show that the population heterogeneity may bring that threshold level down to as few as percent with a similar basic reproduction number. population heterogeneity, it appears, may even outweigh the vaccination in its importance as a factor checking the spread of the disease. we urgently need to fully understand the extent and nature of how people differ in susceptibility to the infection and the ability to spread it and appreciate that in our decision-making. in the long run, a lower number of people infected means fewer causalities to the virus. in the short run, however, lockdown policies around the world take the capacity of the healthcare system into account too. in that context, it is notable that population . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . heterogeneity also reduces the peak levels of the infected population (from percent, as in the homogeneous case, to - percent). lockdown, when well-scheduled, is capable of substantially reducing the cost of the outbreak. the timing of the lockdown is crucial in all scenarios. when prematurely implemented, the lockdown leaves too large a portion of the population susceptible to the infection, which results in the second wave of the epidemic. in such cases, the epidemic may gain momentum and eventually lead to nearly the same total number of infected persons as in the case of no lockdown. the second wave appears to stretch over a more extended period in the heterogeneous cases, which may misguide policymakers in their assessment of the efficiency of the lockdown. too late a lockdown, however, is also inefficient, because it allows for many avoidable infections. in the optimal lockdown strategy, one should wait until the proportions susceptible fall to levels where the instantaneous reproduction number turns unity. after reaching that threshold, the lockdown measures should be implemented with maximal possible strength to cool off the epidemic' momentum and halt the further spread of the virus. to design such an optimal policy response, however, it is mandatory to understand the kinetics of the epidemic well and assess the threshold correctly. that includes accounting for the role of population heterogeneity. designing policy responses to the covid- and other epidemics. our results imply that we should further extend those models to include different predispositions to catch and spread the infection. with optimal lockdown strategy, the total number of infected people may be reduced to as low as five percent in the heterogeneous population. notably, such level of prevalence is of the same magnitude as was found in serological surveys . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint will also be less affected by lockdown measures. that may contribute to the selectivity of the first type and reduction of the eventual cost of the epidemic. on the other hand, closing down public workplaces, introducing strict social distancing, isolation, or public hygiene measures may affect more the superspreaders while having limited effect, if at all, on socially less engaged and initially more prepared people. that may form lockdown selectivity of the second type and exaggerate the cost of the epidemic. which scenarios develop in reality needs urgently being examined while countries move into the postlockdown phases. long-term effects of the population heterogeneity reported here also call for revisiting the policy recommendations with respect to the superspreaders. the usual policy recommendation with respect to the superspreaders is to maximize lockdown efficiency among the superspreaders. yet, we indicate that such a policy may delay but not prevent the second wave of the epidemic and spread, unnecessarily, the infection more into the non-spreaders population. we need to address this issue in designing social isolation policies. the extent and type of population heterogeneity depend on many factors that need to be studied. those include demographic factors such as age and sex, kinship structures and relations, household sizes and roles within them. factors of heterogeneity also include biological predispositions, behavioral patterns (that, in turn, may depend on demographic circumstances, such as the presence of persons vulnerable to the disease in the household or kinship networks), educational, occupational, and income differentials, and others. a better understanding of these relations is instrumental in combating both the current urgency and other communicable diseases. to address those issues, however, we need representative and comparable statistics on how we differ in odds to catch and then to spread the virus. such data are barely available, and we call statistical and healthcare agencies to urgently fill the gap in data on population heterogeneity. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . we incorporate population heterogeneity into the discrete version of the kermack we assume a symmetric model where both the propensity of catching the virus and the propensity of spreading it are proportional to the communicability parameter ݇ . hence, we model new infections as follows: in modeling the course of recovering, we trace the duration of the infection period for the infected people and assume every infected person to recover in time ߬ after getting infected. that is, the number of people recovering in the period ‫ݐ‬ equals: . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . we neglect r-s transitions from recovered to the susceptible population because such transitions have not yet been reported to play a substantial role in the covid- epidemics. we also neglect the fatality of the disease because we intend to highlight the primary effects of population heterogeneity upon the overall course of the epidemic. introducing r-s transitions, mortality, and more realistic demographics should pose no difficulty in future research. assuming the entire original population is susceptible, the number of secondary infections per one initially infected person of type ݆ over the communicability period ߬ may be found from ( ) here, is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint that halt the new infections completely. eqs. ( ) and ( ) lead to the following closedform solution for the evolution of the susceptible population of type the higher the communicability parameter ݇ , the faster is the fall of the susceptible population in ( ) . that creates compositional change in the remaining susceptible population, a change that suppresses the communicability-weighted susceptible population ‫ܬ‬ ሺ ‫ݐ‬ ሻ and checks the spread of the epidemics. in generating and interpreting results of simulation scenarios, it is useful to relate the model parameters to the commonly used basic reproduction number ܴ . to establish the relation, assume the initial distribution of infected people follows the model relation ( ) and is proportional to the weighted populations of each type: that is, the basic reproduction number is the weighted average of the communicability parameter with weights equal to the weighted susceptible populations of each type. at an advanced phase of the epidemic, substantial portions of the population move to infected or recovered compartments, and the instantaneous reproduction number of a new outbreak decreases to: , a new outbreak may be contained without a lockdown. subpopulation is set at such a level that the population-average basic reproduction . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint number ( ) equals . we form the heterogeneous populations in such a way that or percent of infected people are responsible for percent of the further spread of the epidemic, similar to what was reported in the literature [ ] [ ] [ ] . assuming that ‫ݔ‬ percent of infected are responsible for ‫ݕ‬ percent of transmissions, the communicability parameter of non-spreaders (݇ ଵ ) and superspreaders may be found from ( ) as: , in which case our model turns to the conventional sir model. in fig. s , we present sizes of the three population compartments in four selected simulations for the homogeneous population: no lockdown intervention (pane (a)); lockdown reducing the . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. similarly timed (pane (c)) leads to near-optimal results. indeed, such an 'optimality' of the lockdown ignores infection fatality and healthcare systems' capacity that has become a concern in many countries. in fig. s is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . table s . even with only half of the people being non-spreaders, and with no lockdown, the long-term cost of the epidemic and the peak number of the infected people decrease by more than percent as compared to the homogeneous population. in an extreme case where . percent of people are non-spreaders, the long-term cost of the epidemic is only about five percent without any policy intervention. the peak level of the infected population also falls dramatically as the population heterogeneity increases. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . (pane (c)), and the optimal lockdown reducing the spread by . percent that starts at ‫ݐ‬ ൌ (pane (d)). all lockdowns last for days. vertical axis: population size starting with original population. horizontal axis: time in days from the original infection of . percent of people. is the strength parameter of the lockdown; ‫ܫ‬ is the eventual proportion of the population infected throughout the course of the epidemic. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint ) . elife. covid- : a collection of articles a contribution to the mathematical theory of epidemics lessons from a rapid systematic review of early sars-cov- serosurveys experts' request to the spanish government: move spain towards complete lockdown first-wave covid- transmissibility and severity in china outside hubei after control measures, and second-wave scenario planning: a modelling impact assessment how will country-based mitigation measures influence the course of the covid- epidemic? the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application social network-based distancing strategies to flatten the covid curve in a post-lockdown world estimation of country-level basic reproductive ratios for novel coronavirus (covid- ) using synthetic contact matrices health and sustainability in post-pandemic economic policies early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia epidemiological and clinical features of the novel coronavirus outbreak in china the reproductive number of covid- is higher compared to sars coronavirus clustering and superspreading potential of severe acute respiratory syndrome coronavirus (sars-cov- ) infections in hong kong estimating the overdispersion in covid- transmission using outbreak sizes outside china epidemiology and transmission of covid- in cases and of their close contacts in shenzhen, china: a retrospective cohort study #propoirtion of non-spreaders; = for the homogeneous case k <- . #communicability parameter for the non-spreaders k <-r *( +sqrt( + *beta*k *(r -k )/(r ^ *( -beta))))/ #communicability parameter for the superspreaders k<-c(k ,k ) #communicability parameters #ditribution of the population *tau))- #period of the lockdown qq<- . #lockdown efficiency coef. -no lockdown; -absolute halt of epidemic q<-ifelse(horizon %in% quaranteen,qq, ) #generate scenario fun=sum) plot(pt.agr$t,pt.agr$s,type="l",col="darkgreen r if(min(q)< ) rect(min(horizon[q!= ]),- ,max(horizon[q!= ]), ,density= ,col="grey #function generating the epidemic scenario for the given set of parameters covgen<-function ncol=tau) p.k<-p*distr n <-sum(k*p.k) alpha<-step/(tau*n ) k/n ) if(sum(i.k)<i ) { k-i.k i.k<-i.k+(i -sum(i.k))*p :tau]<-i.k/tau i.k<-rowsums(i.matr) effective) for (t in horizon) { q<-q[horizon==t] #lockdown parameter: the lockdown reduces alfa q-fold s.prev<-pkt new i.k<-rowsums(i.matr) s<-s.prev-i.k.new r<-r.prev+i.rec i<-sum(i.k) j<-sum(k*i.k) n<-sum(k*s) r .effective< the epidemic is minimal ‫ܫ(‬ ൌ . percent) when the lockdown is both optimally timed, and strict enough (pane (d)).an even more heterogeneous case where percent of infected people spread the virus in percent of the secondary cases is presented in fig key: cord- -yz buegp authors: gushulak, bd; weekers, j; macpherson, dw title: migrants and emerging public health issues in a globalized world: threats, risks and challenges, an evidence-based framework date: - - journal: emerg health threats j doi: . /ehtj. . sha: doc_id: cord_uid: yz buegp international population mobility is an underlying factor in the emergence of public health threats and risks that must be managed globally. these risks are often related, but not limited, to transmissible pathogens. mobile populations can link zones of disease emergence to lowprevalence or nonendemic areas through rapid or high-volume international movements, or both. against this background of human movement, other global processes such as economics, trade, transportation, environment and climate change, as well as civil security influence the health impacts of disease emergence. concurrently, global information systems, together with regulatory frameworks for disease surveillance and reporting, affect organizational and public awareness of events of potential public health significance. international regulations directed at disease mitigation and control have not kept pace with the growing challenges associated with the volume, speed, diversity, and disparity of modern patterns of human movement. the thesis that human population mobility is itself a major determinant of global public health is supported in this article by review of the published literature from the perspective of determinants of health (such as genetics/biology, behavior, environment, and socioeconomics), population-based disease prevalence differences, existing national and international health policies and regulations, as well as inter-regional shifts in population demographics and health outcomes. this paper highlights some of the emerging threats and risks to public health, identifies gaps in existing frameworks to manage health issues associated with migration, and suggests changes in approach to population mobility, globalization, and public health. the proposed integrated approach includes a broad spectrum of stakeholders ranging from individual health-care providers to policy makers and international organizations that are primarily involved in global health management, or are influenced by global health events. several current emerging threats and risks exposing public health vulnerabilities are linked to global processes, such as economics, trade, transportation, environment and climate change, and civil security. many of these processes are influenced or affected by the migration and mobility of human populations. , international migration, which is a supporting component and a consequence of globalization, increasingly affects health in migrant source, transit, and recipient nations. the flow of populations between locations with widely different health determinants and outcomes creates situations in which locally defined public health threats and risks assume international or global relevance. this fact is illustrated by the rapid awareness, detection, and response to the emergence of a novel influenza a/h n virus in the spring of . , global demographic predictions indicate that the forces promoting and supporting international migration will continue to do so, and may become stronger in all regions of the world as populations attempt to move up gradients of opportunity (such as economic, educational, security, health). both the diversity (the term 'diversity' describes the dissimilarities between host and migrant populations relevant to the determinants of health (such as genetics and biology, environment, behavior, and socioeconomics); 'disparity' reflects the burden of inequalities present at both individual and societal levels, which affects the determinants of health.) and the nature of modern mobility and migration frequently exceed the capacities of and thereby challenge existing policies and programs designed to address migration and health. the goals of this paper are to promote a change in thinking and approach to global health issues that reflects emerging evidence and importance of population-based factors, as opposed to disease or pathogen-based regulatory frameworks that have been traditionally used. this approach focuses on factors of human population mobility and shifting demographics that affect both health determinants and disease outcomes. attention in the public health community is traditionally drawn toward the potential and real effects of infectious diseases associated with migration. common examples observed in nations that receive migrant populations include tuberculosis [ ] [ ] [ ] [ ] and hepatitis b. [ ] [ ] [ ] however, sustained migration between disparate health environments also affects the longer-term epidemiology of chronic noninfectious diseases; this has a downstream impact on health promotion, health services for disease prevention and management, and occupational health outcomes at migrant destinations. as a result of these impacts, migration exerts increasing influence on public health policy, education of health-service providers, health system design, and service delivery. examples of these influences include the need to regulate or manage the use of alternative medicines and pharmaceuticals imported by migrants, or the introduction of alternative medical procedures. [ ] [ ] [ ] in terms of public health, migration has implications for recognition of threats, as well as for surveillance and response capacity. migration also influences broader aspects of the 'health of the public,' including the background burden of chronic or latent diseases (both infectious and noninfectious) and patterns of preexisting immunity; it also influences the use and uptake of disease prevention and health promotion interventions, and health-care service utilization in general. , ensuring that necessary information is both available and understood by diverse communities is an increasingly important aspect of public health planning and preparedness [ ] [ ] [ ] in nations with large mobile populations. this was recently shown by responses to the threat of influenza a/h n importation, which included quarantine, isolation, or preventive interventions. [ ] [ ] [ ] traditional regulatory approaches to public health risks in the context of migration are commonly disease oriented or event based. frequently, these concepts assume or are based on the view that a degree of homogeneity or similarity characterizes migrant populations; they also relate to the administrative or legal status of the population. this article puts forth the observation that many of the important public health aspects of migration originate from or are based on the diversity and disparity of the populations themselves and extend beyond the legal and temporal processes involved in changing one's residence. addressing migration-associated health threats and risks will be more effectively accomplished if approached from this population-based framework, rather than from traditional disease-or immigration status-based views. it is proposed that the development of standardized, programmatic approaches to health and migration that are based on collective international evidence would be an effective strategic and operational approach to global health. failure or further delays in addressing emerging health issues associated with migration and population mobility will continue to impair the effectiveness of policies and programs designed to tackle modern global health challenges. , methods the peer-reviewed literature was accessed through electronic searchable sites (pubmed, promed, and others) using standard search strategies for literature related to migrants, mobile populations, and specific disease outcomes. in addition, publicly available reports from international and national organizations and agencies were accessed for information on migrants, mobile populations, and health. organizations and agencies included the world health organization, international organization for migration, international labour organization, other united nations (un) agencies, world bank, centers for disease control and prevention (atlanta, usa), european centres for disease prevention and control, the health protection agency (uk), and others. in all the literature or reports, population demographics, source country, reporting region, and health outcome measurements were sought. as the study involved no contact with patients or individuals or personal medical information, research ethics approval was not sought. several factors associated with human population mobility make it a significant determinant of future health threats and risks for all regions of the world. these include the number of people on the move, as well as the diversity and disparity of population characteristics between source, transit, and recipient destinations. taken together, these factors exert a significant influence on the globalization of disease threats and risks. a third factor that continues to challenge objective measurement of health outcomes in migrants is the lack of standardization in terminology that applies to mobile populations. doing so would allow correlation and differentiation of populations on the basis of health-risk characteristics rather than administrative categories. part of the growth in migration is simply due to the increase in human population (the rate of growth is no longer increasing). the global population in was estimated at b . billion people. the global population estimate in was . billion. in , it was estimated that there were million international migrants. current estimates of international migrants place their numbers at b million. if this population were considered a national population, international migrants would be the world's fifth largest nation. a report from the un showed that % of all migrants resided in nations; migrants constitute at least % of the total population of nations; % of international migrants live in high-income economies; % of migrants have moved from a low-to-middle income country to a similar economically designated nation; and % of migrants have moved from a low-to-middle income nation to a high-income nation. ('south-to-south' migrants are about as numerous as 'south-to-north' migrants.) of the b million international migrants reported by the un in , b % arrived in the united states alone. these trends can be associated with profound demographic impacts on migrant source and destination countries. these global population figures, although important in their magnitude, also reflect significant differences in the demographic and health determinants of the migrants themselves. there are millions of migrant workers who leave their families behind to be supported by their financial remittances. the migrant worker population is increasingly composed of women, particularly within asia. these population figures also comprise refugees and internally displaced individuals who seek a safe haven and security after fleeing conflict and disaster (see table ). in addition, there are those populations for whom the numbers and statistics are less definitive. this refers to population movements of migrants without legal permission or authority to migrate, who enter and reside unofficially in a host country. the clandestine nature of these unauthorized migrant ('unauthorized migrants' is emerging as the preferred terminology for international migrants who arrive without the necessary approvals, permissions, or documents (such as identification, citizenship cards, visas, passports, and other travel documents). irregular migrants, undocumented migrants, and those who are smuggled or trafficked outside their own country are included in this terminology.) flows, including smuggling and trafficking, makes the determination of their numbers difficult and estimates inexact. the quality of data for unauthorized migrants decreases as the migration process becomes less formally organized. nonstandardized use of terminology describing migrants a major challenge in assessing health impacts of migration is the lack of agreed definitions and consistency in the use of terminology to describe migrant populations over time. some migratory movements may involve international travel across formal boundaries, whereas others, such as rural-urban migration and the internal displacement of populations through conflict or disaster may remain internal national processes. each of the processes and movements can be associated with several descriptive or definitive terms that can vary over time, use, location, and legal or administrative standards. the terminology used to describe a group of migrants in one location, for example, immigrants, may refer to a different migrant group in another setting. in some settings, the term 'immigrant' refers only to those accepted as residents in the destination country and granted legal status to remain there. in other jurisdictions, the term 'immigrant' may be used to refer to any foreign national including those without a formal legal status. although many health risks are associated with movement between locations with different health determinants and outcomes, many definitions of migrant populations currently are based on administrative measures, such as the duration of stay. the un distinguishes migrants according to the duration of stay, classifying them into long-term migrants (residence in a country other than the usual place of residence for months) and short-term migrants (a period of residence of months but o year). this definition does not apply to those individuals traveling for business, to visit friends or relatives, to seek medical treatment, or to undertake pilgrimage. this variability in the use of terminology and lack of direct descriptions related to health creates challenges in the analysis and interpretation of health outcomes associated with migration. international organizations and agencies are attempting to standardize the terminology of migration, but these activities are largely based on administrative and residency principles and may not adequately reflect the health characteristics and determinants of the person or population. furthermore, many modern migration flows are temporary or reciprocal, reflecting the global integration of economic, educational, and labor markets. such movements include populations composed of temporary and seasonal workers, international students, or medical tourists, as well as the growing numbers of those with dual or multiple citizenship and right of residence. these populations, although experiencing and reflecting the health and public health influences of migration, are not systematically captured in traditional national or international immigration statistics. it has been proposed that the health aspects of migration can be better addressed through a standardized, population health-based functional approach rather than by the administrative consideration of processes of modern migration (see table ; modified from gushulak and macpherson ). emerging health threats, risks, and challenges resulting from migration identifying threats related to migrant populations has been driven by historical outbreaks of transmissible infectious diseases of public health significance, such as plague and cholera. as seen in recent years with the severe acute respiratory syndrome (sars, ) and influenza a/h n ( pandemic), many national responses with regard to migrant populations tend to be traditional, on the basis of the principles of border inspection, isolation or quarantine, and exclusion. in migration health, threat and risk identification, assessment and management rarely occur 'pre-event.' examples of poorly studied health threats of potential societal and public health importance include domestic violence against migrant women in destination locations, , long-term impact of dietary changes , on the incidence of cardiovascular disease, diabetes, and certain forms of cancer in foreignborn migrants and their locally born offspring, or the importation of health services or pharmaceutical products from less-regulated environments, representing traditional but often unregulated or unmonitored patterns of self-care. efforts aimed at addressing these challenges can begin through the identification of vulnerabilities within different migrant populations. once identified, demographic and population-based risk analysis can reveal the extent to which mobility globalizes risks for national health systems. some health factors associated with migration are simply a function of the size of the populations on the move, and can be considered as affecting all migrants. there are specific factors associated with vulnerability, risk of illness, and adverse health outcomes that are not equally distributed across migrant groups. they may be relatively more prevalent in some migrant cohorts reflecting uneven influences of behavioral, environmental, genetic, biological, and socioeconomic determinants of health. migrants originating from areas of poverty, those who are forcibly displaced by conflict or environmental calamity, those with limited educational and linguistic skills, and those who are dependent on their communities for protection (such as people with preexisting health conditions, unaccompanied minors, the elderly, the young ,and single-parent families) are at greater risk of adverse health outcomes. at the same time, new arrivals who are subjected to legal, economic, and/or social exclusion can be very vulnerable to contracting disease resulting from poor living environments and exploitative working conditions, including lack of access to health care and preventive services. through a combination of genetic or biological, behavioral, environmental, and socioeconomic determinants of health, many global populations display major differences in the frequency and expression of poor health. the introduction of population movement into an area characterized by sustained differences in measures of population health allows for the transfer or elaboration of these characteristics between locations. this is a concept with far-reaching implications for health maintenance and promotion, disease prevention, intervention and health-services management, and education and training programs. in the sphere of infectious diseases, population mobility is one of the underlying factors in the emergence and reemergence of diseases of international public health importance as shown by communicable disease outbreaks. prevalence disparities between migrant source and destination countries can also exist for noninfectious diseases and conditions, although the direction of disparity from high to low prevalence and vice versa may vary depending on the condition being studied. as a consequence, migrant-receiving nations are sometimes required to respond to adverse health outcomes that originate beyond their jurisdiction and normal planning considerations. in addition, migrants who are subjected to legal, social, or economic isolation and deprivation may develop levels of ill health much different from those seen in the local or host population. taken together, evidence clearly suggests that health interventions and attempts to mitigate adverse health outcomes in migrant communities may require approaches that differ from those required by the locally born community. , the impact of migration on national health and disease epidemiology many economically advantaged nations have gained the benefits of long-standing and effective public health and disease-control programs. the effective control of tuberculosis in much of the high-income world means that the major remaining public health challenges presented by the disease in developed countries are related to migration. in terms of noninfectious conditions and chronic diseases, programs directed at detection and treatment for malignancies (cervical, breast, and colon), interventions to manage anemia and some endocrine disorders, and the significance of maternal-child health issues have resulted in the moderation of the impact of these illnesses locally. migration from less economically advantaged areas will affect the epidemiology of diseases in 'low-incidence' host environments. this is particularly true for diseases that occur at very low incidence levels, or which have been virtually eliminated locally. the relationship between migration and disease epidemiology at the destination of the migrant is not always negative. differential risk and variability in adverse health outcomes may exist between migrant and host populations for a number of diseases. variations in prevalence may go in several directions or vary over time and across generations. health impacts of population mobility may occur in an epidemiologically neutral context. large populations of labor migrants moving within asia or western europe represent situations in which there may be no significant health disparities between mobile and host populations, and any significant migrant effects on health instead are related to the scale of demand for services. finally, population mobility may result in situations in which new arrivals exhibit more positive health characteristics than those observed in the host population. examples of the latter type are observed in the context of some noninfectious or chronic diseases, such as cardiovascular diseases and eating disorders, and are described as representing the 'healthy immigrant effect.' , even this 'healthy immigrant effect' concept varies depending on time, social situation, and clinical condition. although preexisting health conditions and illnesses can be associated with changes in disease patterns, the act of migration can also pose new threats and health risks. postmigration public health impacts include the consequences of ill health when newly arriving migrants experience isolation, social exclusion, and/or poverty. in situations in which migrant communities' access to health or social services is limited, post-arrival susceptibilities may increase, manifested by the expression of a more severe or advanced disease. programs and strategies designed to promote and improve the health of migrants and mobile populations vary between nations. they often reflect national health priorities and local migration dynamics. examples include developing migrant-friendly clinics and hospitals, ensuring that some categories of unauthorized migrants, such as those without documents, can receive care without being reported to immigration authorities, providing medical care or screening guidelines indicating the role had by mobile populations in the epidemiology of a given disease or illness, and in terms of public health risk, considering migrant and mobile populations in emergency and contingency plans for disease risk mitigation. health system challenges migration-associated adverse health outcomes present two sets of challenges to health systems in migrant-receiving nations. the first challenge is the early appreciation and recognition of the diversity and disparity components of the population, which could result in significant migrant health issues. early recognition can be achieved through effective engagement of the health-services system by a health professional or the migrant. the size of the migrant population and the diversity within migrant communities and populations can mask significantly different groups with disease vulnerabilities. health practices may differ significantly by group, particularly in health-promotion strategies and approaches to disease screening between source and host nations (for example, hypertension, diabetes in pregnancy, colon, uterine or breast cancer). these differences may also extend to infectious disease prevention and control measures, such as vaccination or outbreak response. if health indicators are collected or recorded in terms of broad administrative classifications, such as 'migrant' or 'place of birth,' health risks in populations composed of internally displaced, refugees, or trafficked individuals may be obscured. the second set of challenges is related to access to care for migrant populations. even with the recognition of adverse health outcomes in migrant populations, providing secure access to equitable health services for populations of migrants can be difficult. these difficulties can exist even in nations with long-standing immigration programs. for nations that have only recently begun to deal with the growing dynamics of international migration, the difficulties can be much greater. professional and population education, training, and orientation to societal values in health promotion and maintenance, disease prevention, and health services utilization also take time and commitment to achieve. new and evolving populations of migrants and mobile populations can result in rapid arrival and growth of large communities with diverse characteristics, which include social, linguistic, cultural, and economic status; these can be associated with disparate health outcomes. access to and utilization of health and medical services by some foreignborn communities may have a different pattern than those of the host population. , specialized services encompassing linguistically and culturally competent providers, designed for the problems of migrants, will be required to ensure adequate health-care programs and service delivery models. similar features may need to be integrated into public health and disease-control programs designed to mitigate health threats or risks. this is reflected in the need to have educational and instructional information prepared in the language of migrants at an appropriate level for comprehension, and the need for translation or visual tools to deliver messages in a culturally appropriate manner. depending on the location and health sector capacities, these forces can affect the design and function of the health program. migrant-specific programs may be more effective for the migrant community, but they may engender additional costs and resource demands. additional challenges occur as a result of migrant diversity itself and can be seen in many locations where demands or needs for culturally competent health services can extend across several nationalities and ethnicities. strategies to deal with these situations include ( ) support for acculturalization and integration to allow migrants to better use domestic medical and health services and ( ) the provision of migrant-specific or migrant-friendly health services. national, regional, and municipal differences in migrant history and demography make it unlikely that a single approach will be applicable to all venues. however, modern information technology and networking does provide opportunities for the sharing and exchange of best practices and information across cultural environments. , the legal or administrative status of the migrant does affect access to services and care. migrants in an unauthorized situation and some foreign-born women have been shown to have a lower utilization of health services than the local population. for example, health services may be too costly for migrants who do not have health insurance coverage. although linguistically appropriate health services are available and affordable, they may not be used because of migrants' lack of information about their rights and entitlements or out of fear for deportation. limitations to traditional responses to the health challenges of migration traditional approaches to health and migration frequently deal with specific diseases, primarily communicable diseases of public health significance that may be associated with the arrival of migrants. , coordinated attempts at the international level to manage infectious disease transmission were organized and consolidated into the international health regulations (ihr), which was revised in . some nations with integrated and long-standing immigration programs have systematically screened applicants for permanent residency status (immigrants) and some other classes of mobile populations (such as temporary resident applicants, including foreign students or migrant workers ), for various health conditions and illnesses. immigration medical screening, quarantine, and isolation have been used in attempts to address the possible introduction of health threats by exclusion. major immigration-receiving nations continue to use these processes to reduce the impact of health disparities in arriving mobile populations. important as they are from a legal and administrative perspective, programs and policies that continue to embrace responses of inspection and exclusion will be increasingly costly and ineffective in the context of modern migration and population mobility. furthermore, attempting to manage or mitigate health risks in arriving travelers, when many of the health risks may be latent or subclinical, without affecting international travel and commerce is operationally and logistically impractical. modern migration is an integral component of the broader process of globalization and is intimately linked to other nonhealth aspects of globalization, such as global trade and economics, safety and security, and environmental and climatic changes. population mobility underpins the labor and economic demands for human capital. it also helps mitigate the social, demographic, and economic impacts of aging populations in many economically advanced nations where increased migration is required to sustain labor markets and population growth. in addition, modern migration is greater in magnitude and more diverse in health demographics than the traditional immigration process. at present, many people migrate temporarily or travel back and forth between their community of origin and their destination. as international migration will be an increasingly important aspect of human activity, improving the health of migrants and reducing adverse health outcomes related to migration can be expected to be a growing concern globally. some migrant-receiving nations are beginning to appreciate the impact of chronic illnesses in migrants. this includes the demand on and the use of health and medical services by foreign-born populations, and the impact of lifestyle and behavioral factors on health and the health sector. [ ] [ ] [ ] [ ] [ ] standardized approaches to manage health implications associated with population mobility have been proposed, which extend beyond traditional immigration administrative processes to encompass an integrated health framework for modern population mobility (see table ). managing health threats, risks, and challenges in a global context the need for modern and global approaches to population mobility and health is not an abstract goal. considerable attention in the field of migrant health is devoted to the investigation and improved documentation of health indicators among migrant populations in receiving nations. however, many of the health threats, risks, and challenges related to health outcomes due to migration result from factors and influences present outside the jurisdiction and hence the direct influence, of the migrant-receiving nations. , even in nations where long-standing immigration programs are a component of national policies, the health aspects of migration may not be addressed systematically and much of the attention toward migrant health issues is only national in scope. some regional strategies have been proposed, but analysis suggests that they may not be evenly applied or supported. , as a result, there is a paucity of systematic programs and policies to support the health of migrants. to improve global health management and preventive health practices, there is a need for coordinated international actions and partnerships between governments and organizations in nations of origin, transit, and destination. studies have suggested that primary health prevention endeavors such as tuberculosis control in countries of migrant origin are more economical over the longer term than traditional immigration screening programs and policies. they address better universal access in support of equity and the right to health, and have secondary preventive benefits manifested through the improvement of health indicators in migrant source countries. there is growing interest in and appreciation of efforts to address the importance of health and migration at the global level. in , the who world health assembly resolved to take on the issue through its member states by adopting a resolution on migrant health. approaching the topic through coordinated, international action will require considerable changes in many current national and regional health strategies and disease-control policies. national programs based on immigration status, nationality, historical roles of national borders, and traditional travel patterns will need to be redesigned to allow for equitable access to health services for migrants, and greater exchange of information and data to improve research into migrants' health. threats, risks, and challenges will need to be conceptualized in terms of mobility and population dynamics, and to consider migrant origin and transit practices. developing multisectoral approaches the health of migrants is intrinsically linked to all determinants of health but particularly to the unequal distribution of socioeconomic determinants, including income status, housing and accommodation, education, nutrition, sanitation, and employment. , as a consequence, societal responses will be most effective if they are multidisciplinary and involve stakeholders from all relevant sectors working together to reduce adverse outcomes and improve the health of migrants. international dialogue and activities in the field of migration are centered around the principles and policies of more effectively managing migration for the benefit of origin and recipient nations. sustaining and improving the health of migrants is a lateral issue that must be integrated into all aspects of migration management. this implies integrating migration into health policies and strategies that are directly related to desired health outcomes. it implies an increasing awareness among health-care providers and educators, as well as migration policy makers on how to address health threats, risks, and challenges associated with or resulting from population mobility and disparities in health services between geographical locations. a systematic approach to managing adverse migration health outcomes must reflect and integrate the several patchwork policies that have been evolving in many nations for more than a century to deal with situational aspects of migration. at present, various policies exist that address issues related to the health of trafficked and smuggled migrants, labor migrants, those traveling for medical and religious reasons, and for those applying for formal immigration. other broader policy instruments deal with aspects of health for bona fide refugees and asylum seekers or refugee claimants, detained and incarcerated migrants, and for those being returned or deported. integrated health policies that respect the rights of migrants will greatly facilitate coordinated approaches. these must be based on standardized international terminologies and principles reflecting the tools of the un, international organizations, and national programs. systematic actions that support migrant health improvement access to health services, and those that address the specific vulnerabilities of certain migrant populations, will assist nations in developing programs to meet current and future demands. these measures are in the global and national public health interest of sending and receiving communities from a social equity and equality perspective. prioritized programs to reduce disparities responsible for the greatest health risks several of the adverse health outcomes related to migration, particularly those associated with infectious diseases, are already the subject of international and in some cases global attention. many of these diseases are being addressed through initiatives that involve international and regional programs dedicated to improving global health. they include international efforts to expand immunization (gavi), reduce the impact of high-burden diseases (such as tuberculosis, hiv/aids, and malaria), manage the implications of pandemic influenza, and improve public health responses in general (ihrs). although migration and population mobility may feature in some aspects of these endeavors, there is a paucity of integrated collective action on migration-associated components. integrating a migration component into these activities can facilitate the global approach to disease control and demonstrate immediate benefit for both source and recipient nations. mobile populations are one of the means by which locally arising risks can become global challenges. mitigation programs and control strategies must encompass migration components in terms of both threat-to-risk assessment and intervention planning. the importance of these issues has been noted during responses to global health events such as sars ( ) and the more recent pandemic influenza ( ) event, wherein travel-related control measures included screening, inspection, isolation, quarantine, and exclusion. the scale of migration and population mobility has required many of these responses to have cultural and linguistically appropriate services. to be effective, such programs need to reflect the ongoing health impacts of migration that extend well beyond the 'immigration' process. a relatively new phenomenon in international population mobility is the number of migrants who, greatly facilitated by modern travel industry, return to their place of origin to visit relatives or friends; they are known as vfr (visiting friends and relatives) travelers. vfr travelers typically take longer trips, stay in local homes or accommodations, eat locally prepared meals, and take fewer pretravel precautions. many vfr travelers return to their country of origin with children who were born at the new place of residence and lack the immunity their parents acquired before migration. these migrant-related populations of vfr travelers have been identified as being associated with increased adverse health outcomes. , education and training in health and migration processes of migration and population mobility have complex ethical, legal, administrative, and social components that relate to the health of the migrant and host communities. studies have shown that the lack of familiarity with migrant health conditions or the nature of health determinants in migrant communities can negatively affect the effectiveness of care. better understanding of the nature of the health aspects of migration can prevent some adverse health outcomes in international migrants through activities that support the early detection and treatment of health problems in these populations. this is accomplished through early access to and availability and affordability of health care for newly arriving migrants. minimum standards for the provision of linguistically and culturally appropriate tools that assist in health-care delivery , are emerging health-system requirements in some nations. as the world becomes increasingly mobile, multicultural health-care providers in many locations will need to acquire greater capacity to understand, study, and address health needs of migrant communities. migration and international population mobility are facts of global life. the volume of mobile populations within and beyond national boundaries is bringing increasingly high numbers of diverse and disparate populations together. this may occur in areas where traditional administrative approaches to managing migration processes cannot address the health-care needs of migrant populations nor the impacts that these populations may have on transit, recipient, and home communities. addressing the health needs of migrants improves migrant health, avoids stigmatization and marginalization, may reduce long-term health and social costs, protects global public health, facilitates integration, and contributes to social and economic cohesion and development. this paper posits that many of the health challenges associated with modern migration have their origins in the international and global extension of inter-regional disparities in health indicators and determinants. mobile populations provide population bridges across these gaps in health indicators, and effectively globalize risks and negative health outcomes. national and international policies and programs reflecting existing geo-political boundaries represent traditional approaches to dealing with health and migration but are becoming progressively ineffective in the face of migration that is growing in volume and diversity, while extending across locations with disparate health determinants and outcomes. related to specific migrant populations or individual diseases and varying between nations, these traditional administrative approaches may not represent the most effective methods and means of meeting the current or future needs of an increasingly diverse and globalized population. the recent resolution by the who world health assembly reflects the growing international recognition of the importance of the health effects of modern population mobility. addressing migration health needs through a global lens will be best achieved with regional and global strategies that consider public health aspects previously considered to be limited to national needs. policies, programs, and health services for migrants may still be prepared and delivered at a local and national level, but they should be based on and reflect international and global principles and standards. systematic and integrated approaches to migration health, based on global processes and migrants' rights, represent an effective method of managing these issues. globalization: people, perspectives, and progress modernity at large: cultural dimensions of globalization globalization and health: a critical appraisal the signature features of 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organization department of economic and social affairs, population division. international migration vision -forecasting international student mobility a uk perspective towards a fair deal for migrant workers in the global economy office to monitor and combat trafficking in persons trafficking in persons report the opinions expressed in this paper are entirely those of the authors and do not necessarily reflect or represent the positions of any organization to which the authors have been or are currently associated. key: cord- -z twpb authors: mcaloose, denise; newton, alisa l. title: wildlife cancer: a conservation perspective date: journal: nat rev cancer doi: . /nrc sha: doc_id: cord_uid: z twpb until recently, cancer in wildlife was not considered to be a conservation concern. however, with the identification of tasmanian devil facial tumour disease, sea turtle fibropapillomatosis and sea lion genital carcinoma, it has become apparent that neoplasia can be highly prevalent and have considerable effects on some species. it is also clear that anthropogenic activities contribute to the development of neoplasia in wildlife species, such as beluga whales and bottom-dwelling fish, making them sensitive sentinels of disturbed environments. cancer is an important cause of morbidity and mortality in several wildlife species. virus-associated, carcinogen-related and novel transmissible tumours currently impact threatened and protected species. cancer can affect conservation outcomes by reducing reproductive success, altering population dynamics (see glossary) or directly or indirectly leading to population declines. in one species, the tasmanian devil (sarcophilus harisii), high cancer incidence threatens the species with extinction. the links between animal and human health and scientific discovery are long standing. viral oncogenesis is a familiar concept in both animal and human fields of medicine, and the study of animal viruses has led to important insights into the molecular basis of cancer. discovering the transmissible effects of the rous chicken sarcoma virus in (ref. ) led to the eventual identification of the src oncogene and its role in human cancer. identification of the ras oncogene originated from studies of murine leukaemia virus and our understanding of the crucial role wnt signalling pathways have in carcinogenesis resulted from studies of mouse mammary tumour virus . it is likely that animals, including wildlife, will continue to contribute to our understanding of cancer biology in the future. novel allograft tumours in tasmanian devils and dogs may influence the development of beneficial animal and human cancer immunotherapies, and wildlife that develop cancer from anthropogenic factors will continue to act as sentinels for animal and human health risks. what is learned about cancer through wildlife health monitoring will affect conservation of animals and wild places and affect human health, consistent with the one world, one health concept (one world, one health is a registered trademark of the wildlife conservation society) . cancer is a major cause of death in humans. the world health organization estimated that in , . million human deaths globally (approximately % of the total number of deaths) were due to cancer . however, despite its high incidence, cancer as a cause for human extinction is unlikely to warrant much consideration. until recently, the same could have been said for most wildlife species. in the few surveys that summarized wildlife mortality data, trauma and starvation were most frequently reported as causes of death , . however, over the past few decades wildlife health monitoring has increased and we are now gaining an improved -and occasionally alarming -perspective about the presence and impact of cancer in endangered species, such as the tasmanian devil, western barred bandicoot (perameles bougainville) and attwater's prairie chicken (tympanuchus cupido attwateri), and non-endangered species, such as the beluga whale (delphinapterus leucas). evaluating health and diagnosing disease in wild animal populations poses several challenges. as in human medicine, data and sample collection in wildlife is performed by networks of professionals and non-professionals across many disciplines, including veterinarians, veterinary pathologists, biologists, epidemiologists and citizens in field stations, universities, zoos and communities. access to live or deceased animals and sample collection can be complicated by environmental obstacles, such as thick jungle or wide dispersal of animals across oceans and vast savannahs, species-specific adaptations, such as flight, or tissue loss through environmental decomposition, predation or post-mortem scavenging. cancer in wildlife is most commonly detected during post-mortem examination with confirmation through histopathology. advanced cancer diagnostics, such as computed tomography and magnetic resonance imaging that are available for cancer detection and identification in humans are generally not accessible or are unavailable for wildlife. techniques such as immunohistochemical staining are of value but have limited applicability in wildlife owing to the species-specific nature of protein targets and consequently the antibodies required for detection. most animal cancer detection resources and the best developed networks exist in the companion animal and agriculture sectors. relatively limited resources, human or financial, are dedicated to consistent or widespread wildlife health monitoring and disease diagnostics. for these reasons and those listed above, cancer in wildlife goes largely undetected. establishing cancer prevalence is important if we are to understand the effect of cancer in wildlife species and its importance to conservation. however, determining valid cancer prevalence (or prevalence of any disease in wildlife) is not often achieved. most wild animals live and die in anonymity without being documented in census data, without baseline health information or without the causes of morbidity and mortality ever being determined or recorded. an exception to this general rule are small, geographically isolated populations, such as the critically endangered island fox (urocyon littoralis), for which population size and animal health can be feasibly monitored and valid disease prevalence can be established . it is more common to determine disease prevalence relative to a sampled group. for example, beluga whales inhabit arctic and subarctic waters along the coasts of alaska, canada, greenland and russia. the southernmost extent of the range includes an isolated population in the st lawrence river estuary (sle) where population and health monitoring have been ongoing for years . in this population, cancer was the second leading cause of death overall (accounting for % of mortalities) with tumours identified in % of adult animals found dead , a rate that is strikingly similar to that found in humans, in whom cancer is the second leading cause of mortality in the united states and accounts for . % of all deaths . in this case, cancer prevalence was determined for the local population rather than the species. as the sle beluga whales are a well-characterized group, accurate data for epidemiological modelling can be applied to the local population; similar disease prevalence and epidemiological investigations can be performed in captive collections of s c i e n c e a n d s o c i e t y abstract | until recently, cancer in wildlife was not considered to be a conservation concern. however, with the identification of tasmanian devil facial tumour disease, sea turtle fibropapillomatosis and sea lion genital carcinoma, it has become apparent that neoplasia can be highly prevalent and have considerable effects on some species. it is also clear that anthropogenic activities contribute to the development of neoplasia in wildlife species, such as beluga whales and bottom-dwelling fish, making them sensitive sentinels of disturbed environments. animals (box ) . in less well monitored or more dispersed populations, disease prevalence is often estimated from retrospective information in the absence of accurate population data, and in many cases small numbers of animals are assumed to be representative of the species as a whole, a situation that may or may not be accurate. in wildlife with cancer, the focus is generally not on treatment but rather is directed at understanding tumour biology, prevention and intervention strategies in spontaneous tumours, as well as efforts to affect conservation policy or introduce mandatory environmental abatement in anthropogenically induced tumours. research and resources for investigating wildlife cancer are extremely limited and successful outcomes for wildlife are more likely for tumours arising in association with anthropogenic activities and interventions that also affect humans. in one notable exception, intense activity is currently focused on tasmanian devils, in which a spontaneous transmissible tumour is spreading to epidemic proportions resulting in devastating effects on the population. in this case, efforts are underway to manage the remaining animals and develop conservation strategies without which species extinction is predicted. the tasmanian devil survives only on the island state of tasmania, australia, and is threatened by extinction owing to a contagious cancer, devil facial tumour disease (dftd) [ ] [ ] [ ] [ ] . it presents as a focal or multicentric neuroendocrine tumour , that generally affects the face and neck and progresses to cause considerable soft tissue disfigurement; metastasis, most commonly to regional lymph nodes or the lungs, occurs in up to % of the animals . complications associated with tumour growth or metastasis result in a mortality rate of % in affected animals. in the early s, tasmanian devils were considered to be common and the tasmanian devil population was estimated at , individuals ; however, since its first observation in (refs , ) , dftd has decimated the tasmanian devil population resulting in a population decline of % and the listing of the tasmanian devil as an endangered species by the international union for the conservation of nature and natural resources (iucn) in . current disease modelling predicts declines of % across % of territories with diseased tasmanian devils and a % reduction of the entire population over the next years , , . at these rates, extinction is a real possibility. evidence supports a novel mechanism of dftd persistence and spread within the population: allograft transmission. although initial transmission trials are not yet published, transplantation of cultured dftd cells and surgically implanted tumour tissue has produced tumours in unaffected tasmanian devils . further evidence supporting the allograft theory includes failure to identify pathogens (such as a virus) using routine light and electron microscopy . additionally, in all animals studied, karyotype analysis shows rather than chromosomes and consistent genetic aberrations, including loss of both sex chromosomes, no copies of chromosome , loss of copy of chromosome and the addition of unidentified marker chromosomes (m -m ) in tumour cells compared with host cells . furthermore, evaluation of multiple microsatellite and major histocompatibility complex (mhc) loci has confirmed genotypes that are identical in tasmanian devil tumours but differ from their hosts, consistent with an exogenous tumour source . despite having a competent immune system [ ] [ ] [ ] , ease of tumour spread is thought to be related to low mhc class i diversity and limited cell-mediated immunological reaction and activation (rather than the failure of immune cells to proliferate) to tumour cells in tasmanian devils , , . canine transmissible venereal sarcoma (ctvs) is the only other cancer in wildlife known to be naturally transmitted through an allograft ; the unintentional transfer of undiagnosed neoplastic cells through organ transplantation is the only comparison in humans [ ] [ ] [ ] . ctvs was first described and transmitted between dogs in by novinski (reviewed in ref. ). it is a histiocytic tumour that generally affects the external genital mucosa of sexually active dogs and is transmitted during breeding and the licking or sniffing of affected tissue , , . the tumour is locally extensive more often than metastatic and in many animals it regresses within several months; morbidity rather than mortality is therefore more common in ctvs. the tumour is present in free-ranging dogs worldwide and is most prevalent in tropical and subtropical countries . ctvs is thought to have developed in a wolf (canis lupus) or east asian breed of dog to , years ago , [ ] [ ] [ ] , and on the basis of genetic markers, murgia et al. suggest that ctvs arose from a single common ancestral neoplastic clone that subsequently diverged into the two current genetically distinct tumour subtypes that exist in dogs today . similarly to dftd, experimental studies have confirmed that ctvs is a clonal cell allograft. supporting evidence includes transmission trials , common specific chromosomal anomalies, such as tumour markers (in particular the long interspersed nuclear element insertion near myc , ), and genetic comparisons of the mhc, microsatellites and mitochondrial dna between tumour and host cells . impaired differentiation of dendritic cells, downregulation of classical mhc class i and absence of mhc class ii , , (rather than low mhc diversity as in dftd) are recognized as factors in host immune system evasion and successful transmission and progression in ctvs , , . circulating anti-tumour antibodies in affected dogs are implicated in natural tumour regression , , which if complete is associated with subsequent resistance , . recent scientific interest in characterizing immunological reactions between the tumour and host, including the disease monitoring of captive animals, primarily those in zoos and aquariums, reveals a wide range of spontaneous neoplasia across the vertebrate taxa. retrospective mortality studies in two zoos have shown similar rates of neoplasia in captive wildlife to those in domestic animals , . tumours, such as chromatophoromas in snakes , , hepatocellular or biliary carcinomas in bears , , and renal, biliary and apocrine tumours in black-footed ferrets , are known to wildlife pathologists through various descriptions in the literature. unusual tumours, such as kaposiform hemangioendothelioma in a tamarin (sanguinus oedipus) or multilobular osteoma and chondroma in an african wild dog (lycaon pictus) have also been observed (d.m., unpublished observations). in a few situations, management practices for captive animals have been associated with cancer development. for example, subcutaneously implanted microchips used for the permanent identification of individual animals have been associated with soft tissue sarcomas in laboratory mice , and rats , as well as in a few zoo animals -degus (octogon degus), feathertail glider (acrobates pygrnaeus) and egyptian fruit bat (rousettus aegyptiacus) . additionally, melengestrol acetate contraception in exotic zoo felids, such as tigers, lions and jaguars, is associated with a high incidence of mammary gland carcinomas ( % in one report ) and is therefore no longer a recommended method of contraception in these animals. role of tumour and host cytokine expression, such as transforming growth factor-β (tgf-β ), interleukin- and interferon-γ, in this unique canine tumour includes consideration of the potential applicability of ctvs as an in vivo model for developing cancer immunotherapies in humans , . genetic diversity is a common topic of discussion and scientific debate in the conservation community. low mhc diversity is implicated as a factor in disease susceptibility owing to its crucial role in immune system surveillance and resistance to infectious disease; it is of special concern in endangered species, such as the cheetah (acinonyx jubatus). low mhc diversity is thought to be important to the high susceptibility of cheetahs to infectious diseases, such as feline coronavirus and the unusually high acceptance of tissue allografts between cheetahs . low mhc diversity has been implicated in dftd transmission and may have been important in the early development of ctvs . current evidence and disease modelling suggest that transmission of dftd and ctvs occurs in a frequency-dependent , , , rather than a density-dependent manner. in frequency-dependent disease transmission models, transmission rate depends on the frequency of contact with an infected host and is independent of population size (for example, human sexually transmitted diseases are often modelled in this manner). if the modelling is correct, dftd could therefore lead to the extinction of the tasmanian devil despite its decreasing population density. in classical density-dependent disease transmission models (commonly applied to infectious diseases, such as measles or influenza) there is a population threshold below which disease is not maintained in the host , and in which disease disappears in the absence of alternative disease reservoirs. recent modelling by hilker et al. suggests that there are certain conditions under which density-dependent disease transmission could lead to extinction in the absence of reservoirs, such as when there is a strong allee effect as is proposed in the predatorprey relationship between golden eagles and the critically endangered island fox . if dftd transmission were density rather than frequency dependent, extinction could also potentially occur under certain densitydependent conditions. dftd is incurable and unpreventable. in an effort to avoid species extinction, scientists and conservationists are considering establishing isolated assurance colonies of tumour-free animals in geographically restricted areas in tasmania or zoos to guard against ongoing population declines while preventive therapies are developed and tested. it is a race against time to ensure the survival of the tasmanian devil. as the population loses ground to the disease, the tasmanian devil's crucial role as the top carnivorous marsupial in the tasmanian ecosystem and its survival will be challenged by native predators, such as the spottedtail quoll (dasyurus maculates) and eastern quoll (dasyurus viverrinus), as well as introduced species, such as the fox and domestic cat (felis catus) . if efforts fail and the tasmanian devil disappears, the tasmanian devil's role in the tasmanian ecosystem and its contribution to biodiversity will be lost forever and dftd will represent the first known instance of a contagious cancer causing the extinction of a species. the biology of dftd and its devastating and rapid effects on the tasmanian devil population are unique regardless of species. more commonly recognized mechanisms of tumorigenesis in both animals and humans include mutations of proto-oncogenes involved in cell cycle regulation, signal transduction and tumour suppression (such as ras, wnt or p ) or the effects of viral oncogenes, such as src. the effects and implications of oncogenic viruses and mechanisms of tumorigenesis in most wildlife species are poorly understood; however, in some species these issues and the consequences for conservation are in the process of being elucidated. attwater's prairie chickens and western barred bandicoots are endangered largely because of habitat destruction , and, in the case of the bandicoot, introduced predators such as foxes (vulpes vulpes) and domestic cats . wild attwater's prairie chicken populations totalled less than by the mid s and fewer than several thousand western barred bandicoots are thought to survive today . captive breeding programmes in both species were established in the s but have been hampered by cancer-causing oncogenic viruses. reticuloendotheliosis viruses (revs), a group of avian gammaretroviruses that are similar to mammalian type c retroviruses , , are associated with lymphomas in attwater's prairie chickens. revs have been isolated from attwater's prairie chickens at every captive breeding facility . natural infection most often causes runting, immuno suppression or a non-neoplastic syndrome associated with high mortality in young birds and b or t cell lymphomas in adults. experimental infection with rev apc- is oncogenic in japanese quail a decrease in population fitness, such as population decline, at low population density. in the lowest ecological regions (such as the sediment surface) of a body of water. an animal in the order cetacea; includes, whales, dolphins and porpoises. a benign tumour of the intrahepatic bile ducts. tumour of the pigment-producing, light-reflecting cells, xanthophores, erythrophores and iridiphores, in vertebrate and invertebrate species, such as amphibians, fish, reptiles, crustaceans and cepahalopods. an organochlorine insecticide that bioaccumulates in the environment and is carcinogenic. an animal in the orders carnivora or odobenidae (walrus), otariidae (fur seal and sea lion) or phocidae (true seals). marginal and long-term changes in birth, death, immigration, emigration and composition (such as, sex, age and class) of a population. an animal in the families trichechidae (manatees) or dugongidae (dugongs and sea cows). (coturnix coturnix japonica) and specific pathogen-free chickens and turkeys, causing cancer (primarily lymphoma) as early as weeks after hatching in inoculated quail embryos and days and weeks postinoculation in domestic chickens and turkeys, respectively . infected attwater's prairie chickens can be chronically and significantly infected and appear to be clinically healthy for months before disease expression, acting as reservoirs for virus replication and transmission to susceptible birds . western barred bandicoots infected with bandicoot papillomatosis carcinomatosis virus type (bpcv ), a novel oncogenic virus that contains genetic material from both papilloma and polyoma viruses, develop cutaneous and mucocutaneous hyperplasias, as well as papillomas, some of which undergo malignant transformation to squamous cell carcinoma , . in a review of western barred bandicoots with lesions, hyperplasias ( %), carcinomas in situ ( %) and squamous cell carcinoma ( %) were all common, as was the presence of concurrent benign and malignant lesions in individuals ( %) . histologically, positive indirect immunohistochemistry for conserved papillomavirus capsid antigens and identification of viral crystalline arrays in affected keratinocyte nuclei with transmission electron microscopy support a causal relationship between the virus and tumour development . virus-associated debilitation and tumour-associated death in rev-and bpcv -infected attwater's prairie chickens and western barred bandicoots, respectively, have led to limited population growth and are a risk to the survival of each species. the potential for disease transmission from captive to free-ranging remnant populations has implications for release and reintroduction efforts. unlike the situation for attwater's prairie chickens and western barred bandicoots, confirming the effect of virus-associated neoplasia in most wildlife species is often much more challenging. for example, in the marine environment, increases in spontaneous benign and malignant tumours have been identified over the past two decades , - . several viruses seem to have a role in the formation of these tumours but causal relationships remain to be confirmed, and understanding short-and long-term population effects will require ongoing and expanded monitoring. green turtles (chelonia mydas) around the globe are dying from herpes-associated fibropapillomatosis , - . these turtles are listed by the iucn as endangered owing to several factors, including habitat disturbance or destruction, over-harvesting of animals and eggs, boat strike and entanglement in fishing nets that lack turtle excluder devices. in some parts of their range fibropapillomatosis-associated death is now also considered to be a contributing factor to overall population decline. in well-monitored populations, such as those along the coasts of florida and the caribbean and hawaiian islands, fibropapillomatosis is thought to be an epidemic , and dramatic increases in prevalence of as much as % since the early s have been observed , . given its global distribution, some have suggested that the disease probably reflects a worldwide panzootic , , . fibropapillomatosis is most commonly observed in green turtles but has been described for all sea turtle species, including the critically endangered leatherback (dermochelys coriacea) , kemp's ridley (lepidochelys kempii) , and hawksbill (eretmochelys imbricata) turtles. fibropapillomatosis in sea turtles is characterized by benign nodular to papilliferous, fibropapillomas and fibromas rather than fibrosarcomas (which are observed but with less frequency) . tumours generally arise in the dermis but can be found in internal organs, such as the lung, liver, kidney and heart. tumours in non-cutaneous sites may reflect metastasis from primary cutaneous tumours or multicentric development that is secondary to systemic virus dissemination, as the virus has been detected with real-time pcr in tumours in cutaneous and non-cutaneous sites , . herpes viral inclusions are seen with variable frequency in tumour epithelium , , . debilitation and death from fibropapillomatosis occurs when tumour growth interferes with crucial functions such as feeding, sight and mobility. the cause, environmental persistence and mode of natural transmission, as well as the cofactors and mechanisms of tumorigenicity of marine turtle fibropapillomatosis, are under investigation. transmission studies and consensus in the scientific community favours a new chelonian alpha herpesvirus as its cause , . viral dna is consistently found in tumours and tissues of tumour-bearing animals and inoculation of fibroblasts from turtle fibropapillomas has produced fibromas in immunodeficient mice . however, to date this new turtle virus has not been cultured and koch's postulates have not yet been demonstrated. limited experiments on two cultured sea turtle herpesviruses, lung-eye-trachea disease virus and hv , have established that both can persist and retain their infectivity outside the host in the marine environment for up to hours . if fibropapilloma-associated turtle herpesvirus behaves similarly, environmental persistence could be important in natural disease transmission, especially in areas of high turtle density. other factors that could contribute to viral persistence and spread include mechanical vectors, such as leeches, which have been shown to carry sufficient viral loads (up to million copies) to be a potential vector . virus-associated papillomas and carcinomas are also described in several marine cetacean and sirenian species in freeranging and managed populations (table ) . in wildlife, tumours of the genital tract are important if they interfere with successful breeding, pregnancy or parturition. in one study, benign genital papillomas were present in . % of dusky dolphins and . % of burmeister's porpoises , and were considered important enough to interfere with copulation in % of burmeister's porpoises , . genital tract carcinoma is an emerging disease in california sea lions. before the early s, malignant tumours of any type were only rarely reported in pinnipeds , , . however, from to , % of sexually mature sea lions that were found stranded along the californian coast and died during rehabilitation had histologically aggressive, widely metastatic genital transitional cell carcinomas . in a subsequent report, . % of california sea lions that died during a series of unusual mortality events caused by harmful algal blooms from may to october, , had benign or malignant genital tumours . otarine herpesvirus- is the putative cause of genital carcinoma in california sea lions , . this virus is consistently found in tumours examined by electron microscopy or immunohistochemical staining and by pcr of the viral dna polymerase and terminase genes [ ] [ ] [ ] . otarine herpesvirus- is a gammaherpesvirus in the genus rhadinovirus and is closely related to human herpesvirus- (ref. ), the causative agent of kaposi's sarcoma , . interestingly, papillomaviruses cause cervical cancer in women, and human papillomaviruses and are considered to be high risk for the development of malignant cancer , . surprisingly, no papillomaviruses have been detected in sea lion or other marine mammal genital tract carcinomas , . the high prevalence of genital tract carcinomas in california sea lions is unprecedented in any pinniped species. despite apparently increasing cancer prevalence, tumours have not been associated with changes in population growth, which from to has been increasing at an annual rate of approximately . % per year . continued monitoring will be essential to determine long-term population effects, identify causes for high prevalence and establish potential environmental cofactors that initiate or promote tumour development. cancer is a multifactorial disease. in the domestic cow infection with bovine papillomavirus (the cause of oesophageal and rumenal papillomas) and exposure to ptaquiloside (a natural carcinogen in bracken fern) results in the malignant transformation of papillomas to squamous cell carcinoma . a similar interplay may occur between viruses and chemical cofactors in sea turtle fibropapillomatosis (that is, increased incidence of fibropapillomatosis in sea turtles in polluted bodies of water) , or sea lion genital cancer: an % higher level of polychlorinated biphenyls is found in the blubber of sea lions with genital carcinoma relative to those without genital carcinoma . systematic studies assessing the potential direct or indirect roles of these contaminants in tumour development have not been performed. however, the above examples suggest that in some wild populations, carcinogenesis reflects the combined effects of multiple factors, potentially including those from the local environment. high cancer incidence is reported in wildlife populations in environments that are heavily contaminated with anthropogenic chemicals. fish living in industrialized waterways suffer epizootics of liver and skin cancer - . in the population of beluga whales living in the sle, an environment that receives effluent from aluminium smelting facilities , cancer is the second leading cause of death . although several industrial and agricultural pollutants have been recovered from the estuary, polycyclic aromatic hydrocarbons (pahs) are a major concern, as they are recognized occupational hazards and human carcinogens [ ] [ ] [ ] [ ] . causal relationships between wildlife cancers and contaminant exposure are receiving increased attention owing to risks for both wildlife and humans. cancer epizootics have been recognized in many species of fresh water, marine and estuarine fish. the most intensively studied epizootics have occurred in industrialized areas of the united states and canada, such as the great lakes tributaries, including locations considered to be areas of concern (box ), puget sound harbours and bays of the east coast of the united states. these environments are all contaminated by pahs released from steel mills, creosote production plants and petroleum facilities , , , . epizootic tumours reported in these areas include hepatocellular adenomas, hepatocellular carcinomas, cholangiomas and cholangiocellular carcinomas in brown bullhead catfish (ictalurus nebulosus) and english sole (parophrys vetulus) , , epidermal and oral papillomas in brown bullheads and white sucker fish (catostomus commersoni) , and (rarely) squamous cell carcinomas and melanomas in brown bullhead catfish , . most affected species are bottom feeders, which suggests that a benthic lifestyle contributes to high cancer incidence through chronic exposure to contaminated sediment and consumption of contaminated invertebrates. pah profiles from species experiencing epizootic cancer support this theory, as they reflect the pah compounds found in the food items and compound profiles of the sediment in their habitats , , . support for causal relationships between environmental pollutant exposure and cancer in fish has been experimental and observational. fish laboratory models have demonstrated that dietary and intraperitoneal exposure to the pah benzo[a]pyrene (bap) produces hepatocellular or biliary tumours . additionally, skin and liver tumours have been induced by exposure to extracts prepared from pah-contaminated sediment. in one experiment, extracts from environmental sediment samples were painted onto the skin of brown bullhead catfish and this resulted in a % increased incidence of skin tumours over years . in a similar study with the same extract, dietary exposure resulted in both biliary and hepatocellular tumours . striking causal associations have also been made when environmental contamination decreased following closure of industrial facilities along affected waterways. for example, the prevalence of hepatocellular carcinoma in adult brown bullhead catfish living in the black river, ohio, united states, ranged from % to % in the early s . at that time, age-selective mortality owing to the high cancer prevalence nearly eliminated in canada and the united states signed the great lakes water quality agreement to address environmental issues in the great lakes region. in , the two countries designated areas of concern (aoc), locations selected owing to their proximity to urban and industrial centres, contaminated river sediment, potential sewer outflows and runoff from paved surfaces (see figure) . at each location, federal, state and provincial governments developed a remedial action plan (rap), a set of guidelines to abate anthropogenic environmental influences. success and eventual delisting are based on improvements in the chemical, physical or biological integrity of the site. many of the great lakes fish populations affected by high rates of cancer occur in areas of concern. there are many methods of measuring success, but decreases in fish deformity and tumour occurrence are one milestone included in most plans, a recognition that fish serve as sentinels of the health in these habitats. so far, of the areas have been delisted. two additional locations have been designated as areas of recovery. induction of small intestinal neoplasia fish older than years from the population . following a downturn in the steel industry, the coking facility located along the river closed in . pah levels in the sediment declined from , μg per g in to μg per g in . during that time, the incidence of liver cancer in brown bullhead catfish decreased by % and the percentage of -year-old fish in the population tripled . cancer is rarely reported in wild or captive cetaceans, and the literature consists predominantly of single cases of lymphoma, leukaemias and a wide range of other neoplasms (for example, granulosa cell tumours, seminomas, and cholangio, renal, squamous and anaplastic carcinomas) , , . however, beluga whales in the sle exhibit a high rate of cancer. small intestinal adenocarcinoma is the most frequent malignancy seen in sle belugas, in contrast to that observed in other cetaceans , , . additionally, among marine mammals, mammary carcinoma has been reported only in sle beluga whales , . industrial and agricultural environmental contaminants have been identified in the sle [ ] [ ] [ ] [ ] [ ] . high concentrations of bap have also been documented in sle tissue samples, and the concentrations of polychlorinated biphenyls, dichlorodiphenyl trichloroethane, mirex, mercury and lead are much higher in beluga whales from the sle than those living in the arctic , , . after a decline in the population owing to hunting pressures, the sle beluga whales received endangered species status from the canadian government in , but since that time there has been no evidence of population recovery , . comparative mortality data from the isolated sle beluga whales and a population of beluga whales in a less contaminated environment in northwest alaska indicate that beluga whales from the sle die at an earlier age, in part owing to the high rate of cancer , . high environmental levels of bap are proposed as an important factor in tumorigenesis in sle beluga whales; however, this idea is contentious and the role of these agents is under active investigation. bap is a potent procarcinogen, and the site of metabolism and carcinogenesis depends on the route of exposure [ ] [ ] [ ] . mice chronically exposed to oral bap develop small intestinal adenocarcinomas, gastric carcinoma and papillomas of the squamous portion of the stomach , . high environmental levels of bap in the sle, known human carcinogenicity and evidence from animal models has led to the theory that oral bap exposure in beluga whales has a role in their high incidence of intestinal cancer. the proposed source of exposure to bap in sle beluga whales is ingestion. beluga whales dredge the sediment, feeding on large numbers of invertebrates, animals known to bioaccumulate bap , . blue mussels in the saguenay river portion of the sle beluga whale habitat contain bap levels that are times higher than in blue mussels in adjacent habitats . pah exposure induces cytochrome p a (cyp a ) expression in hepatic and extrahepatic tissues and cyp a can serve as a biomarker for pah exposure. sle beluga whales show increased cyp a expression in multiple organs (including the liver, lung, urinary bladder and testis), which is consistent with systemic pah exposure and metabolism , . cyp a activates pahs into carcinogenic metabolites, and in animal models the proximal small intestine contains the highest concentrations of cyp a (ref. ). therefore, in sle beluga whales it has been suggested that ingested bap induces small intestinal enzyme activity, resulting in the high incidence of intestinal neoplasia observed (fig. ) . relationships between tumour development and environmental contamination are strongly suggested by scientific data and circumstantial evidence from wildlife studies. tumour epizootics in fish and the high cancer rate in the sle beluga whale population are important indicators of ecosystem health. care and caution must be applied to the selection of tumours used as environmental indicators. some epizootic cancers are solely viral (table ) or genetic in origin and therefore would not serve as appropriate indicators of environmental contamination. for example, spontaneous nephroblastomas of japanese eels (anguilla japonica) contain a mutant gene with a high level of homology to the human wilm's tumour suppressor (wt ) gene . therefore, only certain tumours can be indicators of environmental contamination and ecosystem health. similarities of high cancer incidence and tumour type between species support the conclusion of common risk factors in shared environments and show the value of wildlife populations as important indicators of environmental discord. wildlife cancer reveals itself as a series of challenges and opportunities for conservation. the above examples include cases in which cancer has limited population growth or has caused population declines through the novel mechanism of allograft transmission, viral oncogenesis and the effects of carcinogenic environmental contaminants. however, the list of examples is short and a more complete understanding of the role of tumours in wildlife population dynamics and the individual and interactive factors that drive tumorigenesis across a wide range of wildlife species is lacking but necessary. health monitoring, disease surveillance and scientific inquiry focused on understanding basic biology and interactive factors in wildlife cancer are crucial to our understanding of wildlife health, the role of cancer in wildlife populations and our ability to identify, assess and mitigate the risks for disease development in wildlife populations. key elements for improving environmental exposure to the procarcinogen benzo[a]pyrene (bap) is thought to have a role in the high incidence of small intestinal neoplasia in beluga whales in the st lawrence river estuary. the proposed mechanism involves intestinal exposure through ingestion of contaminated prey items and sediment followed by induction of cytochrome p a (cyp a ) in small intestinal epithelial cells. cyp a is responsible for oxidation and metabolism of bap to the carcinogen (bap , diol , epoxide). the activated carcinogen preferentially binds dna at the exocyclic nitrogen of the guanine residue, which is required for base pairing, resulting in the potential for g → t transversion during dna replication and disruption of tumour suppressors or proto-oncogenes. current limitations that exist in each of these key activities include identifying, coordinating and expanding existing surveillance networks; increasing and developing capacity for disease diagnostics and epidemiology; securing increased funding for multi-disciplinary scientific research and training aimed at identifying the complex mechanisms involved in wildlife tumorigenesis; integrating human and animal health surveillance systems; creating a unified animal and environmental health database; and improving current relationships, as well as establishing new collaborative relationships with stakeholders and policy makers. expanding the range and scope of each of these activities will have broad and direct benefits for wildlife and also potentially for the environment and humans. early recognition of cancer epizootics in wildlife has the potential to drive timely environmental mitigation and influence environmental policy. building capacity and leveraging expertise across disciplines will result in expanded opportunities for advancing our understanding of normal cellular processes and mechanisms of carcinogenesis as has occurred historically in investigations of wildlife cancer. as we look to the future, there is tremendous opportunity for achieving imagined advances in our understanding of wildlife 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to ebv associated membrane and viral capsid antigens in burkitt lymphoma patients the relation of infection with the hepatitis b agent to primary hepatic carcinoma a virus similar to human hepatitis b virus associated with hepatitis and hepatoma in woodchucks herpesvirus and the lucké tumor isolation of a new type c retrovirus (htlv) in primary uncultured cells of a patient with sézary t-cell leukaemia molecular characterization of a unique retrovirus associated with a fish tumor identification and characterization of an exogenous retrovirus from atlantic salmon swim bladder sarcomas the authors thank d. lyden, w. karesh and t. chang, whose thoughtful suggestions, especially early on, helped shape the content of the manuscript. they also acknowledge d. joly and the anonymous reviewers, whose critical reviews and comments markedly improved the final version. key: cord- - syce n authors: domínguez-andrés, jorge; netea, mihai g. title: impact of historic migrations and evolutionary processes on human immunity date: - - journal: trends immunol doi: . /j.it. . . sha: doc_id: cord_uid: syce n the evolution of mankind has constantly been influenced by the pathogens encountered. the various populations of modern humans that ventured out of africa adapted to different environments and faced a large variety of infectious agents, resulting in local adaptations of the immune system for these populations. the functional variation of immune genes as a result of evolution is relevant in the responses against infection, as well as in the emergence of autoimmune and inflammatory diseases observed in modern populations. understanding how host–pathogen interactions have influenced the human immune system from an evolutionary perspective might contribute to unveiling the causes behind different immune-mediated disorders and promote the development of new strategies to detect and control such diseases. the evolution of mankind has constantly been influenced by the pathogens encountered. the various populations of modern humans that ventured out of africa adapted to different environments and faced a large variety of infectious agents, resulting in local adaptations of the immune system for these populations. the functional variation of immune genes as a result of evolution is relevant in the responses against infection, as well as in the emergence of autoimmune and inflammatory diseases observed in modern populations. understanding how host-pathogen interactions have influenced the human immune system from an evolutionary perspective might contribute to unveiling the causes behind different immune-mediated disorders and promote the development of new strategies to detect and control such diseases. infectious diseases are arguably the main source of evolutionary pressure that humanity has ever confronted. the dispersion of different human communities around the globe has exposed each population to different infectious agents, exerting a selective pressure (see glossary) on them; thus, adaptation to the new environment has favored the selection of the most beneficial genetic variants for the host. as a result, infectious agents have caused the expansion of alleles behind the induction of either protection or tolerance to these diseases; heritable variations, that increased the survival to deadly infectious agents, may have been naturally selected before the hosts had the opportunity to reproduce [ ] . natural selection driven by pathogens is probably more remarkable for those infectious agents that have been among us for a longer time, namely the causative agents of well-known diseases such as leprosy, smallpox, malaria, or tuberculosis. the genetic imprint of pathogen-driven selection depends on the length and the virulence of the infections and also the geographical distribution. the human genome presents more than genetic loci with traces of selective pressure [ ] . this group includes more than immune-related genes with functional variations between populations, which are probably behind the variability of responses to immune-related diseases reported nowadays [ , ] . besides natural selection, other evolutionary mechanisms, such as genetic drift, greatly influence the frequencies of the genetic variants found within diverse populations throughout the world [ ] (box and figure ). with the burst of next-generation sequencing and the development of cutting-edge technologies such as transcriptomics, proteomics, and systems biology, we are starting to witness the great impact of evolutionary processes on human immunity and how the interactions between microorganisms and humans that took place millennia ago might play a fundamental role not only in the response against modern pathogenic threats, but also in the emergence of autoimmune and inflammatory diseases observed in modern populations worldwide. in this review we offer a novel perspective on the role of infectious diseases as agents of natural selection and as forces behind the evolutionary pressure encountered by human ancestors and modern humans in their migrations around the globe. specific genetic variants selected throughout different periods of human history may have influenced immune responses of present-day populations against pathogenic microorganisms and may have played a role in the development of certain inflammatory and autoimmune diseases. the majority of experts agree that africa is where our species originated. genetic studies conducted in diverse contemporary populations suggest connections with ancestors that lived on the continent up to years ago [ ] . human evolution has been constantly influenced by pathogens; therefore, a great number of human genes linked to immune functions and immunity-related disorders have evolved along with humans. the heterogeneity in the immune response to infectious diseases across different populations is under genetic control and is the result of evolutionary processes. genetic variants that have been under evolutionary pressure can contribute to explaining the differences in the susceptibility to diseases observed across different populations. the ancestry of individuals from different populations across the globe greatly influences their possibility of developing certain autoimmune diseases and inflammatory disorders. the lifestyle of western societies affects the symbiotic relationships between humans, viruses, and other organisms and might contribute to the rise of certain autoimmune and inflammatory diseases. pathogens have played a central role as agents of natural selection from those very early days. among various infectious diseases, malaria has exerted the highest evolutionary pressure on the communities across the african continent ( figure ) [ ] . populations remaining in sub-saharan africa have been exposed to malaria for such long periods of time that their genetic structures have been shaped by the severity of malaria (plasmodium sp.) infections. in , allison described that sickle cell disease distribution was confined to africa and was associated with the geographical presence of malaria [ ] . this finding led to the more recent description of the existence of mutations in the hemoglobin-b (hbb) gene as a result of natural selection driven by evolutionary pressure for protection against malaria [ ] (table ) . similarly to hbb, some areas of west africa with a high incidence of malaria the gene variations that pass from one generation to the next are often transmitted as a random process known as genetic drift, while selection of advantageous variants tends to be preferentially transmitted. mutations, genetic drift, migration, and environmental selective pressure are among the fundamental processes behind the evolution of humans. the influence of these mechanisms in the diverse communities that were mobilized and then became isolated, as well as severe external factors such as epidemics, caused successive genetic bottlenecks in populations (see figure in main text) [ ] . human evolutionary studies are currently considered under 'modern synthesis', which merges darwin's ideas of natural selection with theoretical population genetics and mendelian principles, stating that evolution occurs via small genetic changes that are regulated by natural selection [ ] . these beneficial adaptations subsequently expand within the members of a population and become evident in the ancestral specificity and the geographical distribution of the advantageous alleles in the genomes of contemporary humans. genetic bottlenecks occur when the number of individuals in a population is reduced drastically due to a catastrophic event such as an earthquake, a flood, a famine, or the outbreak of an infectious disease. these events limit the genetic variation of a population and can lead to genetic drift. as a result, a smaller population, with a correspondingly reduced genetic diversity, remains to transmit genes to future generations through sexual reproduction. even if this reduction in the genetic diversity is temporary, it can lead to long-lasting effects on the genetic variation of the offspring populations. genetic drift: changes in the allele frequencies of a population over generations due to chance. genetic locus: fixed position on a chromosome (e.g., the position of a gene or a genetic marker). histocompatibility complex: region of approximately kb, located on human chromosome , that contains a large number of genes whose products are expressed as proteins on immune cells. of these genes, the best known are hla genes. introgressive hybridization: incorporation of genes from one species into the genetic reserves of another by interspecific hybridization and backcrossing with the parent species. present a high frequency of hemoglobin-c (hbc) in their populations, which is associated with a - % decrease in the possibility of developing the disease [ ] . this is also the case for the duffy antigen receptor gene (darc) in erythrocytes and single nucleotide polymorphisms (snps) in human leukocyte antigen (hla), which have been associated with protection against plasmodium vivax malaria in certain areas of africa where this disease is endemic [ , ] . another example of natural selection driven by evolutionary pressure for protection against malaria are thalassemia (a and b) pathologies, a group of hemoglobin disorders that presents an incidence of up to % among communities of west africa [ ] . the human casp t c snp, expression of which is restricted to the african subcontinent, south america, and certain areas of asia, can modulate immune and inflammatory responses to malaria by antagonizing interleukin (il)- b and nf-kb signaling in innate immune cells; moreover, caspase -deficient mice (casp -/-) exhibit decreased interferon (ifn)-g production and clearance of the parasite, relative to wild type (wt) infected mice [ ] . however, others have questioned these findings, given that caspase -deficient mice also lack caspase expression, so the effects observed might not be specific to caspase [ ] . mycobacterium tuberculosis (mtb) has caused infections in our species and ancestors for at least years [ ] . this long-standing relationship between humans and mtb probably underlies the large variety of immune-related factors that modulate susceptibility to mtb infection, including vitamin d receptor (vdr), natural resistance-associated macrophage protein (slc a ), tir domain containing adaptor protein (tirap), hla, monocyte chemoattractant protein (mcp- ), and cytokines such as il- and ifn-g [ ] ( table ) . patients with african ancestry present a higher frequency of mtb-related genetic variants than individuals from other populations, including variants in the gene encoding for toll-like receptor (tlr ), mediating cellular responses to bacterial malaria is one of the greatest causes of morbidity and mortality in the history of humanity. most human populations with a long history of endemic malaria have evolved genetic adaptations to malaria parasites due to the strong selective pressure that this infection has exerted. since the parasite infects erythrocytes, the evolutionary pressure has selected genetic variants that affect red blood cells and, therefore, the survival of the parasite as well. genetic variants conferring resistance to the disease have spread through human populations over time, including several abnormal hemoglobins that protect against malaria but usually cause erythrocyte-associated diseases in the populations where these adaptations are prevalent. these factors include the t c polymorphism in the caspase gene (casp ); the hemoglobin b (hbb) and hemoglobin c (hbc) variants; mutations in the duffy antigen receptor gene (darc); thalassemias (a and b); sickle cell disease; and polymorphisms in the human leukocyte antigen (hla) loci. dna nucleotide. for example, an snp may replace cytosine (c) with thymine (t) in a certain segment of dna. selective pressure: phenomenon that alters the behavior and fitness of living organisms within a given environment. it is the driving force of evolution and natural selection. thalassemias (a and b): inherited hemoglobinopathies characterized by a failure in the synthesis of the globin alpha or beta chains. toll-like receptors: family of transmembrane pattern recognition receptors expressed by immune and nonimmune cells that recognize conserved pathogenassociated molecular patterns. they play a pivotal role in innate immunity. transgenerational inheritance: transmission of traits from generation to generation. trends in immunology, december , vol. , no. lipoproteins [ , ] . selective pressure has also shaped the mechanisms that modulate the expression of genes implicated in immune responses against lassa virus, such as il- (il ) and the glycosyltransferase-like protein large (large), suggesting that the natural selection exerted by the virus drove the expansion of genetic variants that enhance immunity against lassa fever [ ] . these examples indicate that infectious diseases have contributed to shaping the genetic landscape of african populations and their descendants, and highlight the great impact of pathogens as an evolutionary force in humans. our homo sapiens ancestors were not the only species to venture out of africa, with other homo species performing a similar migration much earlier, such as homo ergaster, homo erectus, or homo heidelbergensis [ ] . from these early migrations, local populations such as the denisovans and neanderthals evolved [ ] . these lineages were not geographically isolated, but lived side by side with modern humans and interbred with them, leaving a genetic footprint in their common progeny. accordingly, - % of the genome of european and asian populations is thought to derive from these now-extinct hominid lineages [ ] . neanderthals spent close to years adapting to their environment and their immune systems were shaped by the infections they faced. by interbreeding with archaic humans, modern humans incorporated these advantageous adaptations in the genome of their descendants. this was highlighted by different studies that showed that the introgression of diverse genes related to immune functions, such as the oas cluster, tlr , or the histocompatibility complex from denisovans and neanderthals shaped the genetic landscape of present-day eurasian, but not african, communities. genomic sequences and expression data from lymphoblastoid cell lines from individuals of european and african ancestry confirmed that the tlr -tlr -tlr genetic loci, presenting signs of local positive selection and repeated introgression from both neanderthal and denisovan genomes [ ] [ ] [ ] , showed a significantly higher expression in individuals carrying archaic-like alleles than in individuals carrying the nonintrogressed modern human alleles [ , , ] . the expression of these genes has shaped human immune responses against different types of pathogens. for example, the gp protein of the hiv- virus has been recently recognized as a tlr ligand [ ] . in this regard, increased tlr expression has been correlated with higher il- production by the macrophage cell line thp- and higher titers of hiv- in the breast milk of hiv- -infected nigerian women relative to controls [ ] . tlr and tlr form dimers with tlr , triggering immune responses against different types of bacteria, fungi, virus, and parasites [ ] . variation in tlr -tlr -tlr is the major genetic determinant of human interindividual differences in tlr / -mediated responses, including cytokine production to a number of clinically relevant pathogens such as staphylococcus aureus and listeria monocytogenes [ ] (table ). this inheritance from archaic humans may have also left some human individuals more prone than others to developing asthma, hay fever, and other allergies (of snps associated with susceptibility to allergic disease, had a neanderthal or denisovan origin) [ ] , although these associations remain to be fully demonstrated [ ] . these reports demonstrate that by interbreeding with archaic humans, modern humans incorporated a group of advantageous adaptations to the genome of their descendants and contributed to shaping immune responses in modern human populations. the migration of our human ancestors out of africa implied the exposure to different types of infectious diseases (box and figure ). one study tested the responsiveness of human macrophages to pathogenic bacteria in vitro, finding that almost % of the genes present in human macrophages infected with the bacteria salmonella typhimurium or l. monocytogenes present different regulatory responses directly linked to the lineage of the donors and, also, that macrophages obtained from individuals of african origin display enhanced bactericidal activity compared with those from individuals of european lineage [ ] . the trend towards lower inflammatory responses in european populations is strengthened by the fixation of a tlr gene variant that results in lower proinflammatory gene expression in populations with a european ancestry compared with those with an african one [ ] . the largest population differences in gene expression between africans and europeans have been found in the macrophage receptor with collagenous structure (marco), a protein implicated in responses against viral infections and tlr-induced dendritic cell activation [ ] , the chemokine receptor cx cr , which mediates effector lymphocyte functions, and also several ifn-stimulated genes [ ] . west eurasian populations present a high frequency of tirap ser leu snps [ ] . tirap is an adaptor protein in tlr and tlr signaling pathways, involved in inflammatory responses and cytokine production. the heterozygous expression of the ser leu snp is protective against invasive pneumococcal disease, bacteremia, malaria, and tuberculosis, as shown in a case-control study of individuals from the uk, vietnam, and several african countries, and it is associated with lower tlr signaling in humans [ ] . this variant is considered to be a consequence of the natural selection that may have taken place in an early period following the migration of modern humans out of africa [ ] . european populations present a selective adaptation of the ifn gene that allows a high production of ifn-g in infectious scenarios due to the positive selection of ifng variants + g and + t; this suggests the existence of strong environmental pressures linked to higher ifn-g concentrations in plasma during mtb infection in european individuals relative to other populations [ , ] . in line with this, a database meta-analysis showed that individuals expressing the + t/a variant of ifng presented higher susceptibility to tuberculosis mtb infection than individuals without it, which might be considered a putative prognostic factor for the development of tuberculosis [ ] , although this remains to be robustly demonstrated. one of the most interesting aspects of humans is their ability to adapt to almost every ecosystem of the planet. the history of mankind is also the history of millions of individuals wandering around the world, looking for a better place to live. a glimpse to the migratory legacy of humanity around the globe reveals the great impact that the massive population movements defined the world as we know it today (see figure in main text). the distances ancient humans travelled are impressive, from the first hominids colonizing africa to the conquest of the americas in a time when the bering strait was not yet under water. the historical exodus of mankind started almost million years ago with the migration of homo erectus from africa through eurasia. from this event on, relatively isolated human populations evolved separately on different continents, leading to the emergence of different human species, such as neanderthals in europe, the denisovans in asia, and, later, modern homo sapiens in africa [ , ] . h. sapiens first colonized large areas of the continent around years ago [ ] , spread towards the middle east at some point between and years ago, and migrated through eurasia, reaching australia within years [ ] . asian human ancestors went through the frozen waters of the bering strait in two distinct waves to colonize the american continent approximately years before the present time [ ] . when humans ventured out of africa, they faced different types of pathogens than the communities that stayed in the african continent. with time, the series of events faced by diverse populations has generated differences in the immune responses to pathogens in the populations with an african or eurasian origin and which have spread throughout the world. the indigenous populations of south america are descendants of migrating populations of north-east asians that crossed the bering strait around years ago [ ] . five centuries ago, european settlers disembarked on the american continent, bringing a large collection of pathogens such as those causing measles, pneumonic plague, and influenza infections, which the indigenous populations had never faced before. these diseases rapidly spread and caused mortality rates above % [ ] . the consequences of these pandemics are still visible in current populations; one report studied dna from the bones of ancient humans from the tsimshian community, living in the british columbia region in canada until the th century, identifying marks of positive selection in a number of immune-related variants [ ] . specifically, the hla-dqa variant was present in almost the totality of tsimshian individuals, but only in one third of present-day humans studied; this suggested that ancient american genomes were evolutionarily selected to respond to local diseases but not to fight against pathogens brought by the europeans [ ] . another study compiled information on infectious diseases that have killed more than individuals among indigenous communities of the amazonia in the past two centuries, showing that the mortality rates and the incidence of infectious diseases rapidly decayed within the time following the first encounter with the pathogen, compatible with genetic adaptation [ ] . european colonizers underwent purifying selection in situations of intense pressure. such scenarios were documented when dutch colonists migrated to surinam and encountered epidemics of yellow and typhoid fever that caused a % mortality rate among settlers [ ] . variations in the frequencies of c , glo, and hla-b genes among the descendants were not likely caused by genetic drift, but rather, it has been proposed that these populations were probably selected through genetic control of survival to the epidemics [ ] (box ). africans and americans with an african ancestry present a much higher number of genetic variants related to robust inflammatory reactions, increased cytokine secretion, and bactericidal activities compared with the other populations [ ] , including more than genes with traces of recent selection, such as il a and il b gene variants [ ] . the degree of african ancestry, analyzed by fine-mapping analysis refined to the duffy-null allele of rs , was correlated with an increased amount of the proinflammatory chemokines ccl and ccl in plasma relative to controls [ ] . a study involving african american and hispanic american women found that the higher values of c-reactive protein (crp) in blood found in these populations compared with european americans were related to a crp-associated variant of triggering receptors expressed by myeloid cells (trem ) [ ] . moreover, comparison of health record data from individuals with connective tissue diseases, including rheumatoid arthritis and systemic lupus erythematosus (sle), as well as atherosclerotic cardiovascular disease from almost african american and european american adults was conducted; the study reported for the latter, a prevalence of atherosclerotic cardiovascular disease in . % african americans (particularly high in young individuals), relative to . % in european americans [ ] . these studies highlight certain genetic links to inflammatory predisposition/manifestation. however, increased proinflammatory activity is a double-edged sword. in the absence of regular pathogen challenges that require maintained modulation of the balance between inflammation and suppression of the immune response, the organism can overreact to inflammatory stimuli and trigger exacerbated responses. for instance, descendants of african populations generally present higher susceptibility to a variety of autoimmune syndromes such as inflammation-associated carcinomas, lupus, asthma, and multiple sclerosis (ms), the overall prevalence of which is up to three times higher in individuals with african ancestry relative to individuals with european ancestry [ , , ] . there are extensive differences in immune cell gene expression between americans with african and european ancestry. the increased proinflammatory responses observed in american individuals relative to other populations might be beneficial to combatting infections, but might also increase the chances of developing inflammatory and autoimmune disorders, which warrants further investigation. our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms, harboring ten million different microbial genes in the human fecal microbiome [ ] . the microbiome has its own evolutionary scenario across different populations with divergent lifestyles, nutrition, and exposure to environmental agents, generating extraordinary heterogeneity. the ongoing process of 'lifestyle westernization' of different societies has an important impact on the mutualistic relationships between humans and commensal organisms worldwide. african tribes are adopting western subsistence patterns, leading to remarkable changes in the composition of their microbiota [ ] . the comparison of the intestinal flora of the baaka hunter-gatherers and the bantu agriculturalists (both from the central africa republic), with a group of us-born african americans showed a great example of the evolution of the human microbiome [ ] . specifically, the bantu, still engaged in hunting, have a greater bacterial gut diversity than their baaka neighbors, who left the jungle for agriculture, and even more than urbanized westerners (us african-americans) [ ] . this reduced microbiota diversity in western societies has been associated with a higher incidence of the so-called 'diseases of civilization' such as cardiovascular diseases, diabetes, obesity, and autoimmune disorders, which are very unusual in hunter-gatherer societies compared with communities living a western-type lifestyle [ , ] . although viruses are mainly seen as pathogenic agents, they also play a fundamental role in the evolution and maturation of the human immune system [ , ] . approximately % of the human genome is composed of endogenous retroviruses (ervs), sequences derived from past retroviral infections and permanently inserted into different regions of the human genome [ ] . one study showed that ervs played a central role in the induction of ifn-dependent immune responses and that the removal of one or more of these viral dna elements in the hela human cell line severely impaired the recruitment of transcription factors necessary to trigger the expression of ifng against vaccinia virus infection relative to controls [ ] . viruses can also influence the severity of infections caused by other viruses. for example, cytomegalovirus infection in hiv- seropositive humans can potentiate the effects of hiv- infection by expanding the pool of circulating regulatory t cells (immunosuppressive); these were shown to inhibit the proliferation of autologous peripheral blood mononuclear cell the origins of the hiv virus are still a matter of scientific discussion. the most accepted scenario argues that hiv originated in simians and was transmitted to humans in west africa in the s, likely due to local ingestion of ape meat infected with the simian immunodeficiency virus. around , the virus reached wide parts of the continent and finally spread overseas thanks to a group of haitian professors coming back from africa. in the following decades, the virus spread worldwide and generated the pandemic we now know. today, there are approximately million people worldwide living with hiv- /aids [ ] . ccr is a receptor of chemokines that plays a fundamental role in hiv- pathogenesis and it is also one of the most promising targets to restrict the infection, since mutations in this receptor turn individuals resistant [ ] . the ccr -d mutation results in a deletion that eliminates the hiv- co-receptor on lymphocytes, providing robust protection against hiv- and, therefore, aids [ ] . ccr -d allele frequencies reach % in northern europe populations, whereas it is not present in populations with different ancestry, such as east asian, native american, or african groups [ ] . this regional distribution of ccr -d variants is most likely related to a naturally selective episode that struck european populations around years ago and involved a strong infectious agent that also employed ccr [ ]. a mathematical model studying the changes in the european populations in the middle ages suggested yersinia pestis (bubonic plague) as the most probable infectious agent behind the pressure that selected this particular genetic variant [ ] . this is in agreement with the finding that european rroma populations, but not northwestern indian populations that inhabit the area where the rroma originally lived, present signatures of positive selection in tlr -tlr -tlr , which influence cytokine responses in y. pestis infections [ ] . (pbmc) in response to cytomegalovirus infection in vitro [ ] . in one study, patients with chronic hepatitis c virus (hcv) infection and hepatitis a virus (hav) superinfection presented lower titers of hcv rna than patients harboring only hcv, suggesting that hcv replication might be potentially suppressed during hav infection [ ] , although this will still require further investigation. the relationships between humans and pathogenic or nonpathogenic organisms are extraordinarily complex and include tripartite evolutionary interactions between humans and microbes competing with each other. this is the case of parasites that infect other parasites, such as bacteriophage viruses, that can influence the outcome of bacterial infections. for example, in a cohort of individuals with chronic wounds, a report showed that the phage pf, which coexists with pseudomonas aeruginosa in infected wounds, triggered the production of type i ifn, the inhibition of tumor necrosis factor (tnf) production, and the suppression of phagocytosis in human primary monocytes and mouse bone marrow-derived macrophages, dampening the antibacterial response and promoting the bacterial infection [ ] . however, bacteriophages can also provide protection to the human host by directly attacking pathogenic bacteria and by upregulating in human pbmcs the expression of proinflammatory genes such as il a, il b, il , tnfa, cxcl , and cxcl , as shown for several s. aureus and p. aeruginosa phages, including pnm, luz , - , and ge-vb_pae-kakheti [ ] . cooperative relationships between organisms are evolutionary processes themselves. the way microorganisms and their hosts associate can lead to interactions of mutualism, in which the interplay may be so intimate as to provide benefit for each party and influence immune responses against different types of pathogens. a great number of humans live far away from the original settlements of their ancestors and are subject to radically different environmental conditions. between two and three million people with european genealogy suffer from autoimmune diseases, the prevalence of which is also increasing in other populations across the globe [ ]. there is rising evidence that the emergence of autoimmune diseases is associated with the presence of a number of immune-related alleles that have been selected via evolutionary processes; and, furthermore, that the contrasting differences in the prevalence of autoimmune diseases between populations may be a result of different selective pressures [ ] . alleles associated with inflammatory diseases that present marks of modern positive selection include the risk allele fut at rs for crohn's disease (cd) or the risk variant sh b at rs for celiac disease [ ] ; such variants have been linked to the development of several human autoimmune diseases, such as type diabetes, ms, and celiac disease [ , ] . the analysis of the integrated haplotype score [ ] of loci associated with sle that might provide protection against infections, such as tnip , itgam, ptpn , tnfsf , uhrf bp , tet -dguok, and blk, has suggested that these loci exhibit robust signs of positive selection [ ] (figure , key figure and table ). african and asian human populations exposed to trypanosoma brucei or plasmodium sp. have presented positive selection of snps in the apol and fcgr b genes; indeed, by enhancing human macrophage-mediated phagocytosis of infected erythrocytes, despite their association with an sle predisposition, these snps have been associated with protective roles against sleeping sickness and malaria, respectively [ , ] . an analysis of human loci associated with inflammatory bowel disease (ibd) concluded that the majority of the loci associated with cd are also linked with a higher risk of developing ulcerative colitis [ ] ( table ). many of these loci were also associated with the development of other autoimmune diseases, namely psoriasis and ankylosing spondylitis [ ] . pbmcs from individuals carrying the sh b variant rs *a (associated with a risk for developing cd) [ ] presented higher production of il- and il- b after stimulation with lipopolysaccharide or muramyl dipeptide due to enhanced activity of the nod inflammasome pathway relative to controls [ ] ; this has suggested an immune-related role for sh b in the context of bacterial infections, which might help explain the positive selection of sh b approximately years ago [ ] . others found an association between genetic variants in nod , cd , and increased susceptibility to cd [ ] , in line with previous results showing that mutations in nod and tlr /cd are related to an increased risk of developing ibd [ ] . from another angle, changes in hygiene patterns seen in the past two centuries brought vast improvements in sanitation, drinking water, and garbage collection, which greatly reduced the exposure to many infectious diseases. however, these conditions may have reduced the exposure to viral and microbial agents that help the immune system to develop tolerance during childhood. the hygiene hypothesis proposes that the lack of exposure to microbial agents in the early stages of life is related to a higher risk of developing hypersensitivity reactions, based on the fact that children that are exposed to higher amounts of microbial stimuli (e.g., by growing on farms) are less prone to develop allergies and asthma [ , ] . moreover, reduced exposure to infectious agents can have a much wider effect than initially believed. lack of exposure to microbes in childhood can cause aberrant responses to infection and potentiate the effects of etv -runx mutations in the pathogenesis of acute lymphoblastic leukemia [ ] . by contrast, a meta-analysis of six observational studies, including participants, showed a correlation between low helicobacter pylori infection and ms, suggesting that low h. pylori prevalence might be a putative protective factor in ms, although this remains to be experimentally validated [ ] . one study also reported that antibodies against toxoplasma gondii were detected less often in patients with ms compared with healthy controls [ ] . however, these findings warrant further and robust investigation. overall, it is clear that evolutionary processes can drive the fixation of genetic variations that increase (or decrease) our defense against infections upon sensing microbial ligands, but can also lead to a greater risk of developing certain autoimmune diseases in which endogenous ligands can cause tissue damage and inflammation. a growing number of reports suggest that inheritance is not always governed by classical darwinian evolutionary processes. exposure to certain environmental stimuli can cause effects in the progeny of an exposed individual, even though the stimuli are no longer present. this type of transgenerational inheritance might be explained through the effects of epigenetic processes, which are hypothesized to be transmitted through the germline and passed on to the offspring [ ] . for example, the worm caenorhabditis elegans can transmit improved resistance to infections to pathogenic bacteria to their offspring through alterations of the histone landscape [ ] . indian meal moths exposed to low doses of virus are subsequently less susceptible to viral challenge, a protection offered to their offspring as well [ ] . transgenerational inheritance of diverse traits has also been observed in mice, in which the variation of the color of the coat is passed on the next generation [ , ] . offspring of male rats subjected to a high-fat diet present glucose intolerance and reduced insulin secretion, linked to reduced methylation at the il ra gene relative to controls [ ] ; and mice fed scorpions are more resistant to a challenge with scorpion venom than mice on a normal diet [ ] . since infections are one of the strongest factors impacting survival, it is conceivable that transgenerational transmission of traits in mammals, including humans, evolved to improve host defense. the number of studies of the potential role of epigenetic inheritance in shaping the human immune system is still scarce. however, different experiences undergone by certain communities indicate that these mechanisms might be important. for example, the babies of pregnant women who suffered during the early stages of pregnancy (the effects of the dutch hunger winter in ), years later showed reduced dna methylation marks in several genes that control metabolism and cell differentiation during development, such as igf , pim , txnip, abcg , pfkfb , and mettl , compared with their siblings [ , ] . this was related with higher rates of obesity, heart disease, cancer, and depression in individuals whose pregnant mothers suffered the effects of the famine [ , ] . some of these effects seemed to be present in the progeny of this group, that is, in the grandchildren of those who had passed the famine during pregnancy [ ] . the rapid growth in the number of reports covering the impact of epigenetic mechanisms in different human processes warrants further and robust studies on the impact of epigenetic inheritance in shaping the evolution of the human immune system. human immune responses have been shaped by the evolutionary pressure exerted by microorganisms and viruses throughout history. generating a broad range of genetic variations and immune functions in different populations favors the adaptation to new environments and increases the chance of survival of the human species against potential pandemics. much remains to be learned in this exciting field over the coming years in order to identify the main regulatory forces and the time window necessary for the fixation of an advantageous genetic trait in a population (see outstanding questions). the combination of the selective pressure caused by infectious diseases with other evolutionarily relevant processes, such as genetic drift, migratory events, bottlenecks, and introgressive hybridization, contribute to driving the expansion, fixation, or elimination of characteristic immune response-related traits in different populations around the world. these specific genetic variants are able to boost the host response against pathogens by improving the sensing of microbial ligands but can also lead to the development of autoimmune diseases, in which the immune system responds to endogenous ligands and induces abnormal responses targeted against the host's own tissues. of note, it is very difficult to assign certain variants, a specific role in the protection or induction of autoimmunity. to assign changes in the genetic landscape of human populations to certain diseases is an extraordinary challenge. moreover, our species is in constant evolutionary interaction with various microorganisms and viruses. populations of bacteria and their viruses (phages) undergo, under natural conditions, reciprocal evolution in terms of resistance and infection; this, in turn, also affects the evolutionary traits of our immune system. thus, an extraordinarily complex scenario exists in which organisms of different phyla interact, compete, and coevolve, to ensure their own survival. as novel tools, the development and refinement of methods that study large sections of the human genome, epigenome, and microbiota, will help to obtain genome-wide data in diverse human populations, allowing us to follow the evolutionary trails left from the encounters with different organisms, further unveiling the roots of human immunity. high-throughput biotechnology and an expanding computational capacity can enable the study of global population genomics and might contribute to decoding the origin and consequences of functional changes in adaptive alleles down to the single cell level. however, these methods also have limitations associated with the difficulty in linking gene variations to clinical phenotypes and disease, the generation of false positives, or the high number of samples necessary to reach reliable conclusions. expanding the heterogeneity of populations studied for immune gene association studies relevant to disease will be key, as generally, a large focus is placed on certain european or american communities, thus generating results that are difficult to extrapolate to other populations. the knowledge of the evolutionary and genetic basis of human immune traits and their impact on diverse pathologies (e.g., autoimmunity, infections, inflammatory diseases, cancer) increasingly suggests that the genetic basis of disease may be derived from a large number of rare variants of modest effect. the mechanisms described here acquire special importance in the current scenario of world globalization, in which the migration fluxes and the admixture of different populations are reaching unprecedented levels, allowing faster expansion of advantageous alleles. however, these processes may also accelerate the spread of new epidemics, as seen in the cases of hiv infection, or more recently, sars-cov, ebola, and chikungunya viruses; as well as the emergence of multiresistant bacteria and fungi, such as methicillin-resistant s. aureus or candida auris. this is just the starting point to unveil the evolutionary history of the relationships between pathogens, the immune system, and humans. further investigation of the functional adaptations of human populations is warranted to provide a broad picture of the functional consequences of evolution in human immunity. acknowledgments m.g.n. is supported by a spinoza grant of the netherlands organization for scientific research and an erc advanced grant (# ). the funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. we thank laszlo a. groh for which are the strongest evolutionary forces that drive the evolution of the human innate immune system? how long does the genome of a given population take to adapt to a new infectious threat? are the mechanisms of resistance to infection transmitted only via genetic modifications, or can epigenetic adaptations to resistance also be transmitted to the progeny, and under what circumstances? the development of single-cell sequencing technologies has opened new fields of study. how does genetic variation of the expression of a specific variant vary between different cell subsets and how does it affect the overall phenotype of an individual within a population? are there specific immune processes that are preferentially impacted by evolutionary pressures? in western societies we enjoy a life expectancy vastly superior to that of our predecessors, but at the same time, we suffer diseases that they did not suffer. can some of the reasons for these changes lie among some of those bacteria that we have somehow lost in our microbiome? identifying these bacteria and understanding their effects on the human body might be the first step to developing putative therapies based on bacterial restoration. since many of the variants causing autoimmune diseases are linked to an enhanced responsiveness to pathogens that is no longer needed in developed countries, could these genes and their related pathways be employed as targets for new putative therapeutic approaches against inflammatory/ autoimmune syndromes? are other newly described genetic regulatory pathways, such as interfering rna or long noncoding rnas, also influenced by pathogen-driven evolutionary processes in different populations globally? proofreading and correction of the manuscript. we additionally thank srinivas agra for providing the figure icon 'bacteria' as deposited on https://thenounproject.com. natural selection and infectious disease in human populations genomic signatures of selective pressures and introgression from archaic hominins at human innate immunity genes genome-wide identification of regulatory sequences undergoing accelerated evolution in the human genome divergent selection of 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help guide an eventual reopening of society. the intervention is based on: ( ) testing every individual ( ) repeatedly, and ( ) self-quarantine of infected individuals. using a standard epidemiological model (sir), we show here that by identification and isolation of the majority of infectious individuals, including those who may be asymptomatic, the reproduction number r of sars-cov- would be reduced well below . , and the epidemic would collapse. we replicate these observations in a more complex stochastic dynamic model on a social network graph. we also find that the testing regime would be additive to other interventions, and be effective at any level of prevalence. if adopted as a policy, any industrial society could sustain the regime for as long as it takes to find a safe and effective cure or vaccine. our model also indicates that unlike sampling-based tests, population-scale testing does not need to be very accurate: false negative rates up to % could be tolerated if % comply with testing every ten days, and false positives can be almost arbitrarily high when a high fraction of the population is already effectively quarantined. testing at the required scale would be feasible if existing qpcr-based methods are scaled up and multiplexed. a mass produced, low throughput field test kit could also be carried out at home. economic analysis also supports the feasibility of the approach: current reagent costs for tests are in the range of a dollar or less, and the estimated benefits for population-scale testing are so large that the policy would be cost-effective even if the costs were larger by more than two orders of magnitude. to identify both active and previous infections, both viral rna and antibodies could be tested. all technologies to build such test kits, and to produce them in the scale required to test the entire world's population exist already. integrating them, scaling up production, and implementing the testing regime will require resources and planning, but at a scale that is very small compared to the effort that every nation would devote to defending itself against a more traditional foe. number r remains greater than , the virus spreads rapidly until most people have been infected (fig. a) , creating a temporary surge of infected individuals. if, using pharmacological or social interventions, r can be reduced below , then the epidemic collapses (fig. b) , and most people remain uninfected (but still susceptible). because of the exponential nature of epidemics, the outcomes are nearly binary. even when r exceeds one by only a small amount the disease spreads at an accelerating pace, whereas as soon as r falls just below one it rapidly collapses. these two outcomes correspond to two distinct strategies for epidemic control, suppression and mitigation, close variants of which are currently attempted by several asian countries (with different political systems) and western democracies, respectively. in the mitigation model, the goal is to reduce r as much as possible but not below . , hoping to end up with a population that is largely immune, without overwhelming the healthcare system in the process (as in fig. a , but attempting to flatten the temporary surge of infected individuals). this could (but is not guaranteed to) lead to "herd immunity" (see, for example refs. , ), which would limit spread in future epidemics caused by variants of the same virus. however, exponential processes are notoriously difficult to control, particularly in the absence of accurate real-time data and when the effect of policy changes is uncertain. the choice is stark: allowing the disease to spread to a large fraction of a population, however slowly, greatly increases the total number of infected people and would cause a loss of life that most societies will not accept. furthermore, given the difficulties in controlling exponential processes using limited information, even a strongly enforced mitigation strategy runs the risk of overwhelming the health care system and significantly increasing the mortality rate due to the failure to treat every patient optimally (primarily due to the lack of intensive care capacity and sufficient numbers of ventilators). if the healthcare system is overwhelmed, patients must be triaged as in wartime, potentially for extended periods of time. notably, both suppression and mitigation are unstable: the mitigation model might first wreck the health-care system and then (as the public demands harsher controls when mortality rises) also wreck the economy. the suppression model might first wreck the economy and then as public pressure forces a relaxation of control, the virus re-emerges. for many months, both approaches are likely to force a large fraction of the population into quarantine. this is because of the large number of asymptomatic carriers of covid- ; in the absence of population-scale testing, the measures need to be implemented in an indiscriminate manner, affecting the whole population. over time, this will result in severe and unequal economic deprivation. our estimate is that in the united states, gdp per capita is already lower by about usd per month. redistribution can offer some protection for the most vulnerable families, but if a loss of income of this magnitude persists for six or twelve months, it could generate a backlash against the social distance measures that are currently our only weapon for fighting the disease. as a result, epidemiologists are giving serious consideration to scenarios that alternate between lockdown and relaxation that will lead to more loss of life and add to even more economic uncertainty. we can use what we know about the dynamics of disease to suppress this pandemic in a way that is far less disruptive than indiscriminate lockdowns and social distancing. because it is less disruptive, a nation can sustain this approach for as long as it takes to find a safe and effective vaccine or a cure. reducing the disruption will thereby save lives. we know that at low levels of prevalence, testing, contact tracing and quarantine (ttq) is a very effective means of suppression , , because it reduces the effective rate of reproduction close to zero. it is not a feasible strategy for suppressing the virus in the current, higher prevalence conditions faced by most countries because it would demand resources that would overwhelm any health department. in addition, the ttq approach suffers from its own instability. unless it identifies every single person who becomes infected, asymptomatic individuals that are not identified will generate clusters that will not be detected until someone develops a severe infection that requires medical care. if only % of cases are severe enough to be tested after two weeks, a single missed case will lead to an average cluster of new cases before it is found. as a result, once the rate of new cases exceeds the capacity of tracing, even briefly, the epidemic runs out of control and the exponential dynamics make it almost impossible to catch up without imposing a lock-down. some have suggested that an updated version of ttq that relies on modern surveillance technology could be viable because it will not make the same resource demands on the public health system. to be sure, it would be useful for innovators to work toward a working prototype that members of the public could voluntarily adopt. but because no such system has been deployed, even as a prototype, it would be dangerous for policy makers to count on the availability in the coming months of a system that is both effective in slowing the spread of disease and acceptable to most members of society. here, we propose a radically simpler strategy: just test everyone, repeatedly. when someone tests positive, ask them to self-quarantine and provide them public assistance that reduces the burden this imposes on them. this approach relies on a key observation that has not been widely appreciated, namely that what matters is the fraction of all individuals that are identified and quarantined. it follows that testing a small number of individuals with a highly accurate test can be much less effective than testing everyone with a less accurate test. in fact, there is a quantifiable relationship between the reproduction number of a virus, and the efficiency of a population-scale testing strategy that brings the effective reproduction number below . below we use analytical models to derive both an upper and a lower bound on the effectiveness of testing, and demonstrate their real-world relevance using more realistic stochastic models. the approach has several important advantages. first, it will work no matter how high the prevalence of infection might be. second, it does not suffer from the inherent instability of contact tracing. the offsetting disadvantage is that it is a challenge to test at the required scale, but this is not as difficult as it might at first seem. it could be implemented using mass distribution (e.g. regular mail) without returning samples to a central testing site. in fact, the tests required do not even have to be properly "diagnostic." they will not be the basis for any decision about medical care. they only influence the decision to self-quarantine. in the worst case, they may cause people who are not infectious to be quarantined, but this is already true for most people (including the authors) in the baseline lockdown scenario. this is an important feature, as it relaxes the demands on the quality of the test. the test can tolerate many false positives, because the result of a provisionally positive test is that someone self-quarantines for two weeks when they did not have to. false negatives are also acceptable as long as people are retested frequently. although this strategy should be introduced alongside of existing measures, it is a useful exercise to ask what level of testing would be required for this strategy by itself to contain any level of infection. clearly, if a perfectly accurate test were applied to the entire population at once, and those who tested positive were fully quarantined, the epidemic would immediately collapse with no new infections (fig. c) . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint to examine the effects of false negatives and noncompliance, we first make the best case assumption about the timing of the tests: every person who is infected is tested before encountering someone who is susceptible. this limit can be approached, for example, by a very effective form of contact-tracing. for coronavirus, it has been estimated that r = . and uncertain data from quarantine in wuhan suggests that rq = . . using the standard (continuous, deterministic) sir model, the equations in fig. a and methods show that the optimal population-scale testing strategy will succeed if at least two thirds of all new covid- cases are immediately identified and quarantined. if is the true positive rate of the test and is the fraction of the public that complies in the sense that they agree to be tested and follow any instruction to go into quarantine, this bound means that the product must be greater than / . next we do the opposite -assume that the test and compliance are perfect, so = = , and consider the worst-case assumption on the timing of the tests: each day, a randomly selected fraction of the population is tested. under that strategy, we find that testing at a rate equal to ( ! − ) percent of the population per infectious period will ensure that r < (fig. b, methods) . using = . and a two-week infectious period for covid- , this implies that at least % of the population would have to be tested each day. real-world testing strategies could do much better than test at random. for example by implementing procedures that test individuals concurrently within a region; that run the screen as a sweep across a country; that slice the population into groups that are tested in a cycle; or use other variables to predict who is more likely to be infected and to test them more frequently (see methods). because herd immunity and other interventions -including the use of masks or reliance on social distancing -are additive with respect to the testing, any of these effects can lower the required frequency of the tests. for example, fig. d shows the required compliance rate as a function of the strength of other interventions, assuming a fixed false negative testing rate of %. the standard but simple and deterministic susceptible-infectious-recovered (sir) models used to calculate these bounds is based on strong assumptions and approximations, such as random mixing of all individuals. to relax those assumptions, we implemented a more realistic numerical simulation using a stochastic model on a social interaction graph (i.e. a stochastic network seir model) to model two realistic scenarios. we focused on the initial exponential growth phase of an epidemic. fig. a shows a simulation that starts with infected individuals and assumes that the product of the compliance and true positive rate = . . population-scale testing using random weekly tests was started on day , and immediately suppressed the epidemic, which was fully stopped by day . in contrast, without testing, viral spread caused a surge of infections. death rates were . % with testing, and . % without, i.e. a more than three-fold improvement corresponding to . million lives saved in a us-sized population. this demonstrates the power of populationscale testing and quarantine for the suppression of novel viruses. the second scenario modeled a country that exits from a lockdown that has suppressed the growth of a pandemic and a with a small fraction of individuals who are immune (fig. b) . in such cases, new outbreaks will inevitably happen. ttq and periodic lockdowns can suppress these outbreaks, but so can an ongoing process of testing and isolating. in the model, a lock-down was applied from day which nearly extinguished the virus by day . at that point, the lockdown was lifted and social interactions returned to normal, but population-scale testing and quarantine was applied as above. once again, the epidemic was suppressed indefinitely, with total deaths limited to . % of the population. if . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint the lockdown was lifted without population-scale testing, a powerful second wave was generated leading to the death of . % of the population overall. the decreased mortality due to testing after lifting lockdown corresponds to more than one million lives saved in a us-sized population. this demonstrates that population-scale testing can be an effective replacement for periodic lockdown as a sustainable way to prevent the resurgence of the virus. finally, systematic simulation of the parameters of the stochastic model (supplemental figure ) showed that with = / (for example, a compliance of % and test sensitivity of %) testing at least every days on average was sufficient to suppress the epidemic, whereas testing less frequently was not. the scale of screening required for the approach is not unimaginable, as it is within an order of magnitude of the level of screening that is critical for protection of the segment of the workforce that is employed in essential sectors such as healthcare, elderly care, public order and delivery of foods and medicines. furthermore, building a test that could be applied at population scale is clearly feasible using current technology. it could be based on detection of antibodies to the virus . however, as it takes time for antibodies to build, the antibody-test cannot detect cases early. a single test also does not discriminate between current and past infection. making sure that someone is not currently infected requires that an antibody test is performed twice over a period of three weeks, during which the individual must be held in strict quarantine. alternatively, the test can be combined with an rna or antigen test. despite these drawbacks, an antibody test will clearly be part of the solution, as it can detect immune individuals that can continue to work safely in health care or with risk groups. however, in countries where the epidemic is successfully suppressed, the fraction of immune individuals is far too small (e.g. - %) for restoring normal levels of economic activity. furthermore, deploying antibody test at a population scale will be more difficult than using an rna test, as the current approach requires blood samples, which decreases compliance and makes self-testing more difficult. a population-scale test can also be based on viral proteins (technically more difficult but possible ), or viral rna, like the current state-of-the-art diagnostic tests (for example ref. ). technically, few measurements are easier and/or cheaper in biochemistry than determining whether a particular rna species is present in a particular sample. the main technical concern relates to false positives caused by contamination of input samples by the amplified dna from previous tests; this can be simply prevented by well-established procedures. despite the technical simplicity, detecting viral rna in the field at populationscale is difficult to achieve using the same design and strict regulatory framework that is used for tests designed for medical diagnostic purposes. current diagnostic tests for sars-cov- are qrt-pcr assays that require ( ) nasopharyngeal swab collected by a trained nurse, ( ) sample collection in viral transport media, ( ) rna purification, ( ) reverse transcription and quantitative pcr. the test is highly accurate, and the total cost is in the order of $ . such highly accurate testing is critical for accurate diagnosis of cases in a hospital setting. however, due to the very detailed and specific regulation, specialized staff and equipment, and centralized testing facilities, such tests have proven difficult to rapidly scale above thousands of assays in each location. a distributed system of sample collection and testing could, however, conceivably be used to scale qrt-pcr to population levels, particularly when using a regional sweeping approach to limit the number of simultaneous tests needed. the capacity could also be increased to -fold by group testing , a method with a long history of use in public health that was originally designed for syphilis tests, and now commonly also used for optimally efficient detection of defective components in industrial . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint production. although some components of tests are currently limiting due to sudden high demand, scaling up their production is not difficult, as the methodology is based on raw materials that are not scarce (e.g. plastic, sand) and biological molecules (enzymes, nucleotide triphosphates and short nucleic acid primers) that are easily produced either industrially or locally using simple biotechnological processes. we also note that qpcr instruments are currently in short supply, but isothermal tests are available that require only a waterbath (see below). a parallel relatively centralized testing method based on existing dna sequencing technology could also be fielded rapidly. in this approach, viral rna in the samples is used to generate dna sequences containing the virus sequences, a sample dna barcode (to identify each case) and two unique molecular identifiers at both ends of the resulting dna fragment (to count the number of virus rnas per sample and to ensure that patient samples do not get mixed in the reaction), and then sequenced using a massively parallel sequencer. this approach is very scalable, as in principle, a single sequencing instrument that is routinely used in scientific research can report more than a billion results per day. furthermore, in the future, a test based on sequencing - that covers many acute infections could also be used to suppress or even eradicate a large number of infectious diseases simultaneously. this would have significant benefits to humanity, and would be very difficult to achieve using vaccines or drugs that target each infectious agent separately. alternatively, we envisage supplementing the current testing regime with a massproduced home test kit that could be used by anyone, result in a simple easily-understood readout, and be performed without specialized equipment. the test should be as easy to use as a pregnancy test, to ensure maximal compliance. boxes of e.g. tests would be massmailed to all citizens, and a national information campaign would encourage everyone to test themselves weekly. in an infected individual, viral rna is present at reasonably high levels in nasopharyngeal swabs, throat swabs, sputum, and stool for up to two weeks , with the greatest amounts in sputum and stool. sputum might be the ideal source for a home test kit, given the ease of sampling. compliance of the home testing could be increased by both rewards and penalties, and potentially enforced by adding a serial number to each test that needs to be reported together with the test result to collect the rewards. the test result can be open in such a way that the result is clear to everyone. it can also be designed so that it maintains privacy. here, the result (e.g. resulting color, number of bars that are visible) needs to be reported together with the serial number to a central facility to get the answer and/or the cash reward. the open and private approaches can also be combined, to design a test that is open and contains an encoded part that needs to be reported to collect a reward. such designs may complicate the approach, but would allow the healthcare system to obtain data that would facilitate monitoring of the outbreak and large-scale contact tracing. the cash rewards could also be contingent on being regularly tested. anyone found positive would be compelled to self-quarantine, possibly under monetary or criminal sanctions, or using additional rewards for compliance. provided that the test is sufficiently quick, testing could be performed in workplaces, or even in checkpoints exiting areas with high infection rate that are currently under lockdown. our approach is not something that can only be fielded in the far future. in fact, tests suitable for home use have already been developed. in contrast to the commonly used polymerase chain reaction (pcr), which optimally requires an instrument that repeatedly changes the temperature of the reaction, many other "isothermal" detection methods have been developed that operate using a single set temperature, and do not require special equipment beyond what is available in every kitchen (e.g. hot water). for example, an . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint isothermal and colorimetric test has been described , , based on reverse transcription-loop mediated amplification (rt-lamp) technology. this test has several desirable properties: unlike pcr, it does not require temperature cycling; the readout is binary and can be achieved by simple observation; and it can start from crude samples . many other technologies also have the potential to detect viral rna rapidly and isothermally [ ] [ ] [ ] ; these include recombinase polymerase amplification (rpa), transcription mediated amplification, nicking enzyme amplification reaction (near), rolling circle replication, and in vitro viral replication assays. although a population-scale test does not need to be as accurate as a clinical-grade qrt-pcr test (see above), apart from a potential increase in errors due to sample collection, there is no theoretical reason why a self-test based on isothermal amplification would not achieve the false negative and positive rates that are equivalent to the current state-of-the-art methodology. making the necessary reagents at scale is also not difficult. per million people, a µl test requires , liters of reagents, consisting of primers, nucleotides, ph-sensitive dye and enzyme, all of which are easy to make at the required scale. a population-scale strategy has the potential to save many lives, and to buy precious time for a vaccine or an effective drug to be developed. it's important to recognize that in contrast to vaccine and drug development, scaling up testing does not depend on any new scientific discoveries; it is a matter of engineering and logistics only. a field test would synergize with drug treatment, as many antivirals act more effectively when they are given at an early stage of the infection. furthermore, development of field-applicable tests needed for rapid population-level screening will have great benefits in combating epidemics in countries with less developed healthcare systems, and would also help in responding to future epidemics, or variants of the current one. the costs of mobilization of scientific and industrial resources for rapid development of such a test are considerable; however, in our opinion, they are still orders of magnitude lower than the costs of the current suppression and mitigation strategies. although balancing collective goods such as economic activity and public health commonly involve very difficult trade-offs, we believe that such a trade-off is not relevant in this case, and that a population-scale screening policy can be implemented in such a way that will both save more lives and cause less economic and social disruption than the current approach. as there is little overlap with other industrial mobilization efforts, such as scaling up current testing regime, building of ventilators or developing drugs or a vaccine, the increased effort for the development of tests would also have very limited opportunity cost. the development of capacity for population-scale testing would also be an important and relatively inexpensive insurance against other pandemics, or re-emergence of covid- once herd immunity is lost or the virus mutates to evade immunity, vaccines and/or antiviral drugs. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint the authors declare no competing interests. the epidemic was first modelled with a standard (continuous, deterministic) susceptible, infected, removed (sir) model. in addition to the very general assumption that there are a relatively large number of cases, which allows modeling of a partially discrete system using a continuous model, the sir model is based on the following standard assumptions: ( ) the population is fixed, ( ) it mixes homogenously, ( ) the only way a person can leave the susceptible group is to become infected, ( ) the only way a person can leave the infected group is to recover from the disease, ( ) recovered persons become immune, ( ) age, sex, social status, genetics etc. do not affect the probability of being infected, ( ) there is no inherited immunity, and ( ) the other mitigation strategies and testing are independent of each other (for fig. d ). the assumption ( ) leads the sir model to overestimate viral spread, as in reality population has substructure (e.g. families, workplaces) and is geographically separated and contacts are more likely between subsets of the population; this is not expected to materially affect our analysis as our conclusions are not based on the absolute rate of the spread, only on its exponential nature. in addition, we modeled the effect of testing in two ways. the first, maximally effective testing strategy assumed that every individual was tested before they infected another person, leading to the upper bound on testing performance in fig. a-b . under this model, the requirement for collapsing the epidemic is that the weighted average of the basic reproduction number and the reproduction number in quarantine ! must be less than one: here, is the true positive rate of the test and is the compliance (fraction of all tested individuals who actually self-quarantine). using = . and = . for covid- , the product of the true positive rate and compliance must be greater than two thirds: . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . the second, lower bound testing strategy (fig. c-d) was modelled by adding an additional 'detected' state to the model, and adding transitions from infected to detected (with rate ) and from detected to recovered (with rate ). this corresponds to continuous random testing of the population at a fixed rate per person per day. here, the requirement for successful collapse of the epidemic is given by the basic reproduction number (assuming perfect quarantine; fig. d ), as follows. first, the rate equations for the sir model with testing are: rewriting the second equation above as follows: makes it clear that / will be negative (i.e. the epidemic will collapse) only if: note that the ratio / is the basic reproduction number , so that the previous inequality can be rewritten as follows: in other words, the testing rate must exceed a threshold given by the recovery rate and the fraction of susceptible individuals / . in the beginning of an epidemic in a naïve population, when all individuals are susceptible, this reduces further to for sars-cov- , assuming = / (i.e. an infectious interval of two weeks) and = . , the required minimal testing rate would be % of the population per day. as the . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint epidemic progresses, the required testing rate drops as fewer and fewer individuals remain susceptible and herd immunity kicks in. to understand the difference between ( ) testing everyone at the same time, ( ) testing everyone in a time separated manner, or ( ) testing the population by random sampling, it is helpful to consider an extreme case of certainly and completely collapsing an epidemic by testing and quarantine, using a perfect test that detects all infected individuals, and complete quarantine. for optimally achieving this, it is necessary to identify everyone who is infected before they have infected anyone else (denoted efficiency, e = ) and quarantining every infected individual (c = ). this requires obtaining a minimum of n bits of information for a population of size n. in case ( ), this is achieved by testing everyone at the same time with a perfectly accurate test that returns one bit (positive or negative). in this case, e = and c = . however, when tests are separated in time ( ), the order of testing becomes important. the optimal strategy discussed in the preceding section, testing everyone at different times, but before they have had the chance of infecting anyone else also works optimally and collapses the epidemic over a single infectious period. however, most strategies for testing n individuals during time ttest_interval before t have e < , and are not sufficient to completely collapse the epidemic using one testing round, as e depends on the relationship between the order of testing and the order of infections. for example, using a random order of testing allows some individuals that have already been tested negative to become infected during the ttest_interval (the mutual information between test results and person being infected at t is less than one bit). however, some other regimens using a perfectly sensitive test can collapse the epidemic (but not always prevent all future infections): for example, a geographical sweep where infections (individuals) are prevented from crossing a moving test front can be used to identify every infected individual in the population by performing a single round of n tests. in case ( ), random sampling of n individuals, e is always less than . the testing becomes less efficient than testing each of the n individuals at the same time, because some individuals are tested twice, and some not at all; some information is thus not obtained, and some tests do not return information that is completely independent of information returned by other tests (sum of mutual information between all pairs of tests is not bits). in other words, if individuals are selected randomly, during a given time interval, the tests will miss some individuals, and some individuals are tested more than once (this increases true positive rate for those individuals, but this does not make up for failing to catch some individuals entirely). considering the extreme case of immediate collapse, it may appear that testing in a time separated manner or by using random sampling will not work because non-concurrent testing can permit infections to cross the testing boundary, and random sampling clearly leaves some cases undetected. however, this very intuitive idea is incorrect, as collapsing an epidemic only requires that the rate of generation of new cases per current case is less than one. the limit for random testing can be obtained using the sir model extended with testing (sir+t), which abstracts away individuals and thus can (only) be used to investigate the effect of random, time-separated testing. analytically from this model, as shown above, the < condition is true when tests are performed at a rate that is higher than − tests per mean infectious period. the same limit results from the following consideration: reducing to less than one using the method representing the lower bound -a completely random testing regime -requires that an infected individual has less than an equal probability of (a) infecting another individual over (b) being tested and quarantined or recovering from the infection (analogously, in sir+t, the combined testing and recovery rate needs to be higher than the rate of new infections). events (a) can recur, but either event (b) terminates the chain. therefore, at r = there will be on average one (a) event, which requires that the order of the infectious and protective events are randomly ordered with respect to each other, with equal density. this yields − tests and one recovery per infections per infectious period, and an upper limit of tests per infectious period at infinity (because as → ∞ the expectation value for becomes the geometric series ∑ %& outside of the theoretical consideration of = , multiple population-scale tests are always required to collapse the epidemic in the absence of other interventions that achieve the same aim. performing multiple tests over time imposes an additional constrain on optimality -the allocation of tests to each transmission interval. as described above, best performance of continuous testing and quarantine is thus achieved when testing is performed immediately after infection for each individual, or as requirement for exiting quarantine. testing blood before transfusion to prevent transmission of hiv or hepatitis c, testing at border crossings, conditional opening of lockdown, or some regimes that apply contacttracing may come close to approximating this limit, which for covid- is = ( " − )/ " = . per mean infectious period; fig. ). however, in most scenarios, such testing efficacy is difficult to maintain over time (because contact is lost, and the unknown infectious intervals rapidly become randomly distributed over time). this level can thus be considered an upper limit of performance of any scenario applied at population scale. using a test whose true positive rate of and testing everyone at the same time performs as well as the optimal strategy. as test sensitivity decreases, the performance of the concurrent regime becomes lower than optimal. however, concurrent testing still performs well above the lower limit obtained from the random testing model. the required pc rate to bring r < using concurrent tests has a simple relationship with the exponential growth of infectious cases. over interval t-t , pc > -(infectious cases at t )/(infectious cases at t). however, it is not as simple to relate this to original r , because the relationship between r and growth rate is a function of the distribution of the generation intervals (ref. ). estimating at r = . using even probability distribution of infections over time, the infected population becomes approx. eight times larger in a single day infectious period. this means that a testing regime that is regularly spaced at day intervals should have pc value of > / = . to bring r < . this is confirmed using empirical simulations to assess the rate of exponential growth in the complete absence of immunity and all other types of interventions; the limit = at = . with testing every infectious period ( days) is reached when ≈ . (compared to . for testing each individual directly after infection). the required testing interval at = . and = . in the absence of other interventions and immunity is , and . days for concurrent testing, testing each individual randomly once during each testing period, and continuous random testing, respectively. these considerations can be summarized as follows: the order of testing efficacies is: everyone before they have had a chance to infect anyone > everyone at the same time > everyone once during a period > testing by random sampling -with population-scale testing . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint remaining feasible and cost-effective by one or more orders of magnitude across all these regimens. the sir model fails to account for several key properties of real epidemics, such as social and geographical population structure, the discrete and stochastic nature of infection and disease progression, and the fact that testing cannot be instantaneous. to account for such more complex real-world phenomena, we implemented a stochastic network model using the gillespie algorithm for accurate numerical simulation of the stochastic dynamics. we used the seirsplus python package (https://github.com/ryansmcgee/seirsplus), which models an epidemic on a social graph, where each individual transitions between six states: susceptible, exposed, detected-exposed, infectious, detected-infectious, and recovered. the two detected states are used to model the effectiveness of testing and quarantine, and social distancing is modelled by removing edges from the initial social graph. we used a random social graph of mean degree (median ) and two-sided exponential tails, which was reduced to mean degree for social distancing (lockdown) and quarantine. the population consisted of , individuals. in both shown scenarios we assumed that the test had % sensitivity, and epidemic parameters were modelled loosely after covid- . detailed source code with comments and parameter settings for each model are available in the accompanying jupyter notebook at https://github.com/paulromer /ubiquitous-testing. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . inequality that must be true to suppress transmission. for the epidemic to collapse, the weighted average of the natural reproduction number " and the reproduction number in self-quarantine ! must be less than one. here, represents the test true positive rate (fraction of all infectious individuals detected), and the rate of compliance. (c) parameters for a sir model with testing and a detected state. (d) requirements for testing to collapse an epidemic in the sir model with testing, expressed in terms of the testing rate required in a population where all individuals are susceptible, with inverse infectious interval . (e) parameters for the discrete, stochastic seir model on a social graph. each compartment was modelled for every individual on the social graph. (f) outcomes of ten simulation runs of the stochastic seir model on a social graph, showing total number of deaths as a function of the fraction tested every day, assuming compliance and true positive rate = / . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . severe social distancing (lockdown) is applied after days, and then lifted after days. population-scale testing is implemented after day (left) or not implemented (right). in all panels, shaded colored regions indicate policy regimes, and the total number of dead individuals is indicated in the sub-panel titles. for both panels, the product of compliance and test efficacy was set to = . and the testing rate was set to = / . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint supplemental figure | successful testing strategies under the stochastic seir model on a social graph. growth curves (daily new cases) showed that given = / , testing at least every days successfully flipped the sign of the exponential growth curve from day (when testing started), whereas testing every days was insufficient. red dashed curves, piecewise exponential fits for days - , - , and - . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint coronavirus disease (covid- ) situation report - impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand pandemics: risks, impacts, and mitigation the basic reproduction number (r ) of measles: a systematic review emerging infectious diseases and pandemic potential: status quo and reducing risk of global spread scientists say mass test in italian town have halted covid- there substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov ) evolving epidemiology and impact of non-pharmaceutical interventions on the outbreak of coronavirus disease in wuhan serological assays for emerging coronaviruses: challenges and pitfalls platinum nanocatalyst amplification: redefining the gold standard for lateral flow immunoassays with ultrabroad dynamic range detection of novel coronavirus ( -ncov) by real-time rt-pcr. euro surveillance : bulletin europeen sur les maladies transmissibles clinical presentation and virological assessment of hospitalized cases of coronavirus disease in travel-associated transmission cluster rapid colorimetric detection of covid- coronavirus using a reversetranscriptional loop-mediated isothermal amplification (rt-lamp) diagnostic platform rapid molecular detection of sars-cov- (covid- ) virus rna using colorimetric lamp development and validation of reverse transcription loop-mediated isothermal amplification (rt-lamp) for rapid detection of zikv in mosquito samples from brazil isothermal nucleic acid amplification techniques and their use in bioanalysis isothermal exponential amplification techniques: from basic principles to applications in electrochemical biosensors isothermal amplification of nucleic acids metagenomic sequencing with spiked primer enrichment for viral diagnostics and genomic surveillance a vision for ubiquitous sequencing loeffler . : diagnostic metagenomics contributions to the mathematical theory of epidemics--i. counting absolute numbers of molecules using unique molecular identifiers the detection of defective members of large populations test everyone, repeatedly to defeat covid- . medium medium.com/@sten.linnarsson/to-stop-covid- -test-everyone- fd eb b covid- mass testing facilities could end the epidemic rapidly infectious disease model with testing and conditional quarantine how generation intervals shape the relationship between growth rates and reproductive numbers we thank many colleagues for comments on the early version of the work. we are especially grateful to drs. minna taipale, mikko taipale and paul pharoah for review of the draft of manuscript. a draft of this paper was initially released as a public preprint (ref. ) , and supporting, independently developed model reported by p.r. on www.paulromer.net. we also note that during the writing of this work, we became aware of two independent analyses, one by julian peto (ref. ), and the other by a team consisting of david berger, kyle hirkenhoff and simon mongey that report similar conclusions (ref. ) . key: cord- - zbvgvk authors: kühnert, denise; wu, chieh-hsi; drummond, alexei j. title: phylogenetic and epidemic modeling of rapidly evolving infectious diseases date: - - journal: infect genet evol doi: . /j.meegid. . . sha: doc_id: cord_uid: zbvgvk epidemic modeling of infectious diseases has a long history in both theoretical and empirical research. however the recent explosion of genetic data has revealed the rapid rate of evolution that many populations of infectious agents undergo and has underscored the need to consider both evolutionary and ecological processes on the same time scale. mathematical epidemiology has applied dynamical models to study infectious epidemics, but these models have tended not to exploit – or take into account – evolutionary changes and their effect on the ecological processes and population dynamics of the infectious agent. on the other hand, statistical phylogenetics has increasingly been applied to the study of infectious agents. this approach is based on phylogenetics, molecular clocks, genealogy-based population genetics and phylogeography. bayesian markov chain monte carlo and related computational tools have been the primary source of advances in these statistical phylogenetic approaches. recently the first tentative steps have been taken to reconcile these two theoretical approaches. we survey the bayesian phylogenetic approach to epidemic modeling of infection diseases and describe the contrasts it provides to mathematical epidemiology as well as emphasize the significance of the future unification of these two fields. molecular phylogenetics has had a profound impact on the study of infectious diseases, particularly rapidly evolving infectious - Ó elsevier b.v. doi: . /j.meegid. . . agents such as rna viruses. it has given insight into the origins, evolutionary history, transmission routes and source populations of epidemic outbreaks and seasonal diseases. one of the key observations about rapidly evolving viruses is that the evolutionary and ecological processes occur on the same time scale ). this is important for two reasons. first, it means that neutral genetic variation can track ecological processes and population dynamics, providing a record of past evolutionary events (e.g., genealogical relationships) and past ecological/population events (geographical spread and changes in population size and structure) that were not directly observed. second, the concomitance of evolutionary and ecological processes leads to their interaction that, when non-trivial, necessitates joint analysis. arguably the most studied infectious disease agent to date has been human immunodeficiency virus (hiv) and it has been the subject of thousands of phylogenetic studies. these have shed light on many aspects of hiv evolutionary biology, epidemiology, origins, phylogeography, transmission dynamics and drug resistance. in fact, the vast body of literature on hiv makes it clear that almost every aspect of the biology of a rapidly evolving pathogen can be better understood in the context of the evolution of the virus. whether it is retracing the zoonotic origins of the hiv pandemic or describing the interplay between the virus population and its host's immune system, a phylogenetic analysis frequently sheds light. although probabilistic modeling approaches to phylogenetics predate sanger sequencing (edwards and cavalli-sforza, ) , it was not until the last decade that probabilistic modeling became the dominant approach to phylogeny reconstruction. part of that dominance has been due to the rise of bayesian inference (huelsenbeck et al., ) , with its great flexibility in describing prior knowledge, its ability to be applied via the metropolis-hastings algorithm to complex highly parametric models, and the ease with which multiple sources of data can be integrated into a single analysis. the history of probabilistic models of molecular evolution and phylogenetics is a history of gradual refinement; a process of selection of those modeling variations that have the greatest utility in characterizing the ever-growing empirical data. the utility of a new model has been evaluated either by how well it fits the data (formal model comparison or goodness-of-fit tests) or by the new questions that it allows a researcher to ask of the data. in this review we will describe the modern phylogenetic approach to the field of infectious diseases, and particularly with reference to bayesian inference of the phylogenetic epidemiology of rapidly evolving viral pathogens such as hepatitis c virus (hcv), hiv and influenza a virus. the review is separated into two main sections. in section we discuss phylogenetic methods for reconstructing the history of infectious epidemics, including identification of origins, dating of common ancestors, relaxed phylogenetics and coalescent-based population dynamics. in section we review epidemiological models and finish by outlining progress in the development of phylodynamical models that marry statistical phylogenetics with dynamical modeling. the introduction of an efficient means of calculating the probability of a sequence alignment given a phylogenetic tree (known as the phylogenetic likelihood; felsenstein, ) heralded the beginning of practical phylogenetic tree reconstruction in a statistical framework. at around the same time the coalescent was introduced: a theory relating the shape of the genealogy of a random sample of individuals to the size of the population from which they came (kingman, ; see section . for details). both of these advances have been subsequently developed to the point that, together they enable the estimation of viral evolutionary histories and past population dynamics. bayesian inference brings together the likelihood, pr(djh) (the probability of the data given the model parameters) and the prior, p(h) (the probability of the model parameters prior to seeing the data), so that the posterior probability of the model parameters (h) given the data is: in a standard phylogenetic setting, the probabilistic model parameters include the phylogenetic tree, coalescent times and substitution parameters, and a prior probability distribution over these parameters must be specified. by using kingman's coalescent as a prior density on trees, bayesian inference can be used to simultaneously estimate the phylogeny of the viral sequences and the demographic history of the virus population (drummond et al., (drummond et al., , , see box ). extension of phylogenetic inference methods to accommodate time-stamped sequence data (rambaut, ; drummond et al., ) and relaxation of the assumption of a strict molecular clock (thorne et al., ; kishino et al., ; sanderson, ; drummond et al., ; rannala and yang, ) provided sophisticated methods for ancestral divergence time estimation. for virus species that occupy more than one host species (e.g influenza a), models that aim to detect cross-species transmission may provide clues to the origin of a virus strain in a host population (reis et al., ). when a new epidemic emerges, one of the first goals is to trace it back to its genetic and geographic origin. the reconstruction of phylogenetic trees to infer the evolutionary relationships has been a key tool to uncover the origin of regional epidemics such as those resulting from hiv (gao et al., ; santiago et al., ) , hcv markov et al., ) and sars coronavirus (sars-cov) . some studies have also attempted to use phylogenetic trees to draw conclusions about transmission history and geographic spread of viral epidemics (motomura et al., ; santiago et al., ; gilbert et al., ) . however, great care should be taken when coming to conclusions about aspects of the epidemic process that are not explicitly modeled in the reconstruction of the phylogenetic tree and even if they are, the user needs to consider the appropriateness of the underlying model assumptions. one common and straightforward method used to identify the origin of an epidemic involves determining the non-epidemic genotype or lineage most closely related to the epidemic, i.e., the molecular sequences clustered most closely with the epidemic strain on a phylogenetic tree. while the method is intuitive, its success heavily depends on the collected data. the closest simian immunodeficiency virus (siv) relative of hiv- is sivcpz (gao et al., ; santiago et al., ) , which is harbored in chimpanzee sub-species pan troglodytes troglodytes and p.t. schweinfurthii in the form of the respective sub-species specific siv lineages sivcpzptt and sivcpzpts. although sivcpz became the prime candidate for the zoonotic source of hiv- as soon as it was identified, alternative sources could not be ruled out due to the paucity of identified chimpanzee infections (vanden haesevelde et al., ) . the source of hiv- was confirmed much later after the collection of sivcpz from fecal samples of wild p. t. troglodytes apes in the cameroon forest . hiv- groups m and n are much more closely related to sequences from the fecal samples than previously identified sivcpz strains. this finding uncovered the distinct origins of hiv- group m (pandemic) and group n (non-pandemic) traced to chimpanzee communities of southeastern and central cameroon respectively. the precise geographic identification of these wildlife chimpanzee reservoirs of hiv- by phylogenetic techniques provided the crucial evidence that sivcpz gave rise to the hiv/aids pandemic. conversely, if strains sufficiently closely related to the epidemic strain cannot be identified then phylogenetic trees are not able to easily provide answers about origins. for example, there has been much heated debate on the origin of the h n influenza a pandemic -whether its source was avian, non-human mammalian or even human. the uncertainty mainly stems from the absence of sequences from the immediate ancestral source population of the virus (gibbs and gibbs, ) . a similar, though less severe problem has been encountered with the search for the origin of hiv- o group. strains of hiv- o group have been revealed to be most closely related to sivgor found in western lowland gorillas (gorilla gorilla gorilla) takehisa et al., ). however, hiv-o sequences are moderately divergent from the known sivgor sequences and consequently, the route of transmission that has given rise to hiv- o group and sivgor is still indeterminate. the interspersion of an emergent viral strain with other strains in a phylogenetic tree is often interpreted as evidence supporting multiple independent viral introductions. for example, hiv lineages are paraphyletic with siv lineages creating several separate clusters of hiv suggesting multiple zoonotic viral transmissions into the human population (santiago et al., ; keele et al., ) . while it is intuitive that separate clusters of the emergent virus suggest multiple introductions, it is not clear from the number of clusters alone how many independent events are responsible for the observed pattern. incomplete taxon sampling will lead to undercounting. for example, there may exist an unsampled sequence that will split an emergent viral cluster, or an additional unsampled emergent cluster. both scenarios, if detected, would increase the lower bound of the inferred number of events. the number of events could also be incorrectly estimated due to phylogenetic estimation error. finally, in situations where the event is potentially reversible, such as with drug-resistance mutations, e.g., adamantane resistance in h n influenza virus (nelson et al., ) , it is quite possible that reversions are also present in the phylogenetic history, and these are not always detectable by a simple parsimony reconstruction, again leading to undercounting. for all these reasons, the applications of bayesian modeling of phylogeography and character evolution on phylogenies is crucial to quantitatively assess the uncertainty generated from these different sources of error (see section . ). in contrast to hiv- , it has been clearly established for almost two decades that the progenitor of hiv- is sivsm from sooty mangabey (cerocebus torquatus atys) (hirsch et al., ; gao et al., ) . it was suggested by (santiago et al., ) that the geographic origin of hiv- groups a and b are in the eastern sooty mangabey range according to the clear geographic clustering displayed in the phylogenetic tree and branching position of the hiv- strains. although this heuristic approach to locating phylogeographic origins is commonly used, it has several disadvantages aside from the sampling error mentioned earlier. first, it relies on strong geographic signals to produce an unambiguous geographic clustering pattern in the trees. second, the lack of a formal statistical framework results in an inability to quantify the associated uncertainty with the geographic estimates. a number of statistical phylogenetic methods aim to reconstruct the migration process by treating geographic locations as another state that evolves down the tree. the states are either discrete (lemey et al., b) , denoted by names of cities or provinces, or continuous represented by the latitude and longitude of the location (biek et al., (biek et al., , lemey et al., ) . even with comprehensive sampling, using a single phylogenetic tree is insufficient to reflect the complex genetic origin of virus species that undergo recombination or reassortment. reassortment arises when segments of the viral genome come from different viruses, while recombination also requires the genetic material from one source to (break and) join with that from another. these two processes enable the generation of novel combinations from two existing genotypes. moreover, these often large genetic changes may provide the potential for adaptation to a new host species (parrish et al., ) . reassortment has played an important role in the evolution of the influenza a virus (lindstrom et al., ; holmes et al., ; nelson et al., ) . evidence for recombination have also been found in dengue (holmes et al., ) , hiv, hcv and sars-cov . there are many phylogenetic methods that aim to detect recombination by identifying discordance in the topologies of different parts of the alignment (grassly and holmes, ; salminen et al., ; lole et al., ; smith, ; robertson et al., ; paraskevis et al., ) , which is a potential consequence of recombination. most of these methods use a sliding window approach to compute a summary statistic along the length of sequence. phylogenetic approaches are based on estimating either (i) bootstrap values or (ii) clade posterior probabilities for each window and a sudden change in bootstrap value, clade posterior probability or site percentage identity is an indication of the presence of a breakpoint around the region. other methods explicitly estimate the position of the breakpoint in an alignment, providing access to test the strength of support for recombination (holmes et al., ) . finally, some approaches portray the evolutionary history by networks to incorporate horizontal transfer (huson, ) or ancestral recombination graphs (bloomquist and suchard, ) . as a rule, rna viruses mutate rapidly, so that viruses isolated only a few months apart may exhibit measurable genetic differences (drummond et al., a and references therein) . indeed, the mutation rate of some rna viruses is so high that it can result in evolutionary changes within a host during the course of infection. this is particularly true of long term chronic infections caused by viruses such as hiv and hcv. it is therefore not appropriate to consider the analysis of sequences that have been sampled years apart as if they are contemporaneous. sequence data with this type of temporal structure are called heterochronous and from such data the substitution rate can be estimated and divergence times calibrated to a calendar scale. here, a tree with branch lengths in calendar units is termed a ''time tree''. fig. depicts an example of a serially sampled time tree of a rapidly evolving virus. to account for temporal structure in sequence data, the earliest methods estimated the time scale by estimating a gene tree with unconstrained branch lengths and then performing a linear regression of root-to-tip genetic distance against sampling times (see for review drummond et al., b) . this method was used to provide the first estimate of the time of the most recent common ancestor (t mrca ) of hiv- m group, placing it in the s (korber et al., ) . despite its simplicity, this method also accurately estimated the age of the oldest hiv sequence sampled in . a maximum likelihood based method (the single rate dated tips (srdt) model; rambaut, ) , estimates ancestral divergence times and overall substitution rate on a fixed tree, assuming a strict molecular clock. the srdt model was used to date the most recent common ancestor of hiv- subtype a in ± and that of subtype b in ± (lemey et al., ) . using the serial coalescent as a tree prior in bayesian coalescent methods (drummond et al., (drummond et al., , drummond and rambaut, ) allows the time scale to be simultaneously estimated with other phylogenetic and demographic parameters. recently, a relaxed clock bayesian coalescent analysis that included two historical viral samples from (zr ) and (drc ) (worobey et al., ) , pushed back the estimated t mrca of hiv- m group to hiv- m group to ( hiv- m group to - . besides estimating the time of an epidemic outbreak, it may also be important to know how long the ancestors of the epidemic strain had circulated in the source population prior to the epidemic. this can sometimes be indicated by the length of the branch ancestral to the epidemic clade. in the case of the swine-origin influenza a virus, the length of the branch leading to s-oiv strains is estimated to be - years depending on the viral segment analyzed, suggesting roughly a decade of unsampled diversity (smith et al., ) . to estimate the age of the common ancestor of sivsm strains, the t mrca of hiv- /sivsm has been dated, indicating that the common ancestry prior the zoonosis of hiv- group a and b spans only the last few centuries (wertheim and worobey, ). this does not necessarily indicate that sivsm first arose only centuries ago, just that the common ancestor of all current sivsm may be recent. however, even this conclusion has recently been questioned (worobey et al., ) as a result of independent calibration evidence that suggests the t mrca could in fact be greater than , years ago, leading to debate about the fidelity of the statistical substitution models commonly employed for divergence time dating when the true divergence times are very ancient compared to the sampling interval. as demonstrated by wertheim and pond, , substitution models that do not take into account the effects of selection can produce underestimated branch lengths leading to much younger age estimates in presence of purifying selection. this will be more problematic for data sets for which the total sampling interval is only a small fraction of the total age of the tree. while incorporating sampling dates provides additional information to phylogenetic inference, it also implies that the reliability of those dates has a heavy impact on the validity of the inference. the h n influenza virus that re-emerged in was found to have missed decades of evolution and was genetically remarkably similar to the h n virus (nakajima et al., ) . it is thus thought to be descended from a strain that was kept frozen in an unknown laboratory for perhaps decades before again becoming a ''wild'' strain again (zimmer and burke, ). if the missing evolution is not corrected for, analyses including the re-emergent strains produce biased date estimates and increased variances of the t mrca of the re-emergent lineages and across the phylogeny (wertheim, ) . in cases where the sampling dates of sequences are contentious or unknown, a method that can handle sequences with unknown dates is required. for example, the leaf-dating method estimates the unknown date or age of a sequence as a parameter, treating it the same way as the age of internal nodes (drummond et al., c; nicholls and gray, ; shapiro et al., ) . unrealistic sampling dates may also be the result of human error and are thus not recognized prior to an analysis. therefore, diagnostics for unrealistic dates are important to pick up errors in the recorded dates. one possible method is to plot the root-to-tip genetic distance against sampling year if the virus does not display significant departure from constant rate (wertheim, ) . another is to check calibrations by dropping each calibration point in turn and re-estimating the date to confirm that the estimated dates are consistent ryder and nicholls, ) . early methods that accommodated heterochronous data assumed a strict clock model. however, a comprehensive study of heterochronous rna viral sequences using the srdt model (rambaut, ) demonstrated that the majority of the rna viral species studied rejected the constant rate molecular clock hypothesis (jenkins et al., ) . the unrooted phylogeny is the other extreme of the scale of rate variability across branches of a phylogenetic tree. neither of them is a realistic representation of the underlying evolutionary process and the reality lies somewhere between the two. this has spawned the development of numerous methods that relax the molecular clock assumption and differ in their assumption of the pattern of rate variation across the branches. the local clock model approach assigns different rates to clades/ regions of the tree. however, without external information, it is difficult to know a priori what is the best partitioning of the tree into local clock models. bayesian model averaging overcomes the challenge of rate assignment by averaging over all possible local clock models , estimating the substitution rates, and the number and position of changes in substitution rate, simultaneously. another category of relaxed clock models is based on 'rate smoothing', including non-parametric rate smoothing (sanderson, ) , penalized likelihood (sanderson, ) and bayesian autocorrelated relaxed clock methods (thorne et al., ; kishino et al., ; aris-brosou and yang, ; rannala and yang, ) . these methods restrict the rates on parent and descendant branches to be similar by penalizing large departures from parent branch rates. hence, rate variation is expected to occur through small and frequent changes. different bayesian autocorrelated clock models differ in the distribution used to model a branch rate given its parent rate (thorne et al., ; kishino et al., ) . however, analysis of sequence data from influenza a and dengue- do not provide any evidence of autocorrelation of branch rates suggesting that autocorrelated models may not be appropriate when analyzing a genealogy of sequences from a single virus species. whereas lineage-effects may be expected to cause autocorrelation of rates (through incremental changes to life-history, metabolic rate et cetera), the gene-specific action of darwinian selection will also cause apparent rate variation among lineages, by producing a general over-dispersion of the molecular clock over the entire phylogeny (takahata, (takahata, , . this second source of rate variation among lineages may be better modeled by uncorrelated relaxed clock models , which make no assumption about the autocorrelation of rates between ancestral and descendent branches. published analyses have provided strong evidence supporting the uncorrelated relaxed clock model (e.g., salemi et al., ; worobey et al., ) over the strict clock model. as well as estimating the age of ancestral divergences, it is also of interest to estimate the time of cross-species transmission if the disease is zoonotic in origin. one method of identifying the time of the host-switch is by applying non-homogeneous substitution models. the motivation of non-homogeneous substitution models is to acknowledge possible differences in pattern of substitution in the virus within different host species, which violates the assumptions of homogeneity and stationarity underlying the standard substitution models. therefore it may be more appropriate to apply different substitution models to different parts of the tree (forsberg and christiansen, ) . non-homogeneous substitution models permit the equilibrium frequencies, and hence the model parameters, to change on a branch and all the descendant lineages from the point of change are assumed to have different equilibrium base frequencies to the lineages prior to that point. this technique has been used to suggest that the immediate ancestral population of influenza a virus resided in a mammalian host (reis et al., ). however, it does not indicate whether the most recent common ancestor of the swine influenza virus and the virus resided in humans or other mammals. interpretation of estimated divergence times can be difficult. there may be direct ancestors that are more ancient, but the lineages that would reveal them have not been sampled or did not survive to the present due to processes such as genetic drift. therefore, the estimated t mrca may not answer the question of interest. for epidemics that resulted from a zoonotic transmission, the host switch event is of paramount interest, but estimating the t mrca of the epidemic strain does not directly estimate the time of the transmission, and only serves as a lower bound. likewise, if there have been processes causing a loss of genetic diversity in the past or the sampling is not comprehensive, then the estimated t mrca could be substantially younger than the age of the viral lineage. an obvious example of the former occurs in seasonal influenza due to seasonal population fluctuations and also strong positive darwinian selection caused by immune surveillance (fitch et al., ; bush et al., ) , leading to rapid lineage turnover and a recent common ancestor of any single-season sample. similarly, the analysis by worobey et al. ( ) shows that the t mrca of hiv- group m seems to have been pushed back due to the inclusion of an additional pre-epidemic sample from which is highly divergent to the sequence (zr ). in general the inclusion of older samples can increase the estimated age of root by (i) revealing previously unsampled lineages that are outgroup to the t mrca estimated without them, or (ii) simply because more temporal sampling breaks up long internal branches as well as potentially revealing ancient evidence of variants that were assumed modern, resulting in a slower estimated rate and therefore older estimated root height. finally, it is likely that current techniques alone cannot always recover accurate divergence dates in the distant past, as illustrated by recent analyses suggesting a much deeper history of siv (worobey et al., ) than previously suggested (sharp et al., ; wertheim and worobey, ). fig. illustrates the problem with three estimated viral time-trees that have vastly different inferred ages of their most recent common ancestor. we would expect the greatest confidence in the inferred age of the human influenza a time-tree where the sample period is a large fraction of the total age of the time tree, and the least confidence in the inferred age of the hepatitis c time-tree in which the sampling period is a small fraction of the inferred age of greater than years. so, apart from better models of rate variation across lineages (see guindon et al., , for early steps in this direction), future research in divergence time dating will likely focus on models that more accurately account for purifying selection and its role in maintaining the structure and function of the encoded genes. the impact of darwinian selection is expressed both in distortions of the genealogy (o'fallon, ; o'fallon et al., ) and the substitution process (e.g., bloom et al., ; cartwright et al., ) from neutral expectations. consideration of the action of pervasive purifying selection is especially important in viral genomes prone to clonal interference and which are compact, information rich and subject to great levels of functional and structural constraint in their evolutionary trajectories, especially when considering long time periods. beyond that there is also a need for more statistically rigorous methods of incorporating diverse sources of calibration information, such as biogeography, archaeology and paleontological evidence. bayesian statistical frameworks are uniquely suited for this sort of integration of multiple sources of information. genealogy-based population genetics can be used to infer demographic parameters including population size, rate of growth or decline, and population structure. when the characteristic time scale of demographic fluctuations are comparable to the rate of accumulations of substitutions then past population dynamics are ''recorded'' in the substitution patterns of molecular sequences. coalescent theory can therefore be combined with temporal information in heterochronous sequences to uncover past epidemiological events and pinpoint them on a calendar time scale. kingman's coalescent (kingman, ) describes the relationship between the coalescent times in a sample genealogy and the population size assuming an idealized wright-fisher population (fisher, ; wright, ) . the original formulation was for a constant population, but the theory has since been generalized to any deterministically varying function of population size for which the integral r t t nðtÞ À dt can be computed (griffiths and tavaré, ) . parametric models with a pre-defined population function, such as exponential growth, expansion model and logistic growth models can easily be used in a coalescent framework (see fig. and box for details). for example a ''piecewise-logistic'' population model was employed in a bayesian coalescent framework to estimate the population history of hcv genotype a infections in egypt . this analysis demonstrated a rapid expansion of hcv in egypt between - , consistent with the hypothesis that public health campaigns to administer anti-schistosomiasis injections had caused the expansion of an hcv epidemic in egypt. the coalescent process is highly variable, so sampling multiple unlinked loci (felsenstein, ; heled and drummond, ) or increasing the temporal spread of sampling times (seo et al., ) can both be used to increase the statistical power of coalescentbased methods and improve the precision of estimates of both population size and substitution rate (seo et al., ) . however in many virus species, the entire genome acts as a single locus, or undergoes recombination only when the opportunity arises through superinfection. the lack of independent loci therefore places an upper limit on the precision of estimates of population history. in many situations the precise functional form of the population size history is unknown, and simple population growth functions may not adequately describe the population history of interest. non-parametric coalescent methods provide greater flexibility by estimating the population size as a function of time directly from the sequence data and can be used for data exploration to guide the choice of parametric population models for further analysis. these methods first cut the time tree into segments, then estimate the population size of each segment separately according to the coalescent intervals within it. the main differences among these methods are (i) how the population size function is segmented along the tree, (ii) the statistical estimation technique employed and (iii) in bayesian methods, the form of the prior density on the parameters governing the population size function. in the 'classic skyline plot' (pybus et al., ) each coalescent interval is treated as a separate segment, so a tree of n taxa has n À population size parameters. however, the true number of population size changes is likely to be substantially fewer, and the generalized skyline plot (strimmer and pybus, ) acknowledges this by grouping the intervals according to the small-sample akaike information criterion (aic c ) (burnham and anderson, ) . the epidemic history of hiv- was investigated using the generalized skyline plot (strimmer and pybus, ) , indicating the population size was relatively constant in the early history of hiv- subtype a in guinea-bissau, before expanding more recently (lemey et al., ) . using this information, the authors then employed a piecewise expansion growth model, to estimate the time of expansion to a range of - . while the generalized skyline plot is a good tool for data exploration, and to assist in model selection (e.g., pybus et al., ; lemey et al., ) , it infers demographic history based on a single input tree and therefore does not account for sampling error produced by phylogenetic reconstruction nor for the intrinsic stochasticity of the coalescent process. this shortcoming is overcome by implementing the skyline plot method in a bayesian statistical [ , ] and represents a significant fraction (% . t mrca ) of the overall tree height, but still small enough that the estimated root should be viewed with caution. (c) a phylogeny of human influenza a subtype h n : the sampling interval spans . years [ . , . ] and represents almost the full height of the tree (% . t mrca ), and all divergence times are likely to be quite accurately estimated, since interpolation between many known sample times is inherently less error prone than extrapolation to ancient divergence times. framework, which simultaneously infers the sample genealogy, the substitution parameters and the population size history. further extensions of the generalized skyline plot include modeling the population size by a piecewise-linear function instead of a piecewise-constant population, allowing continuous changes over time rather than sudden jumps. the bayesian skyline plot (drummond et al., ) has been used to suggest that the effective population size of hiv- group m may have grown at a relatively slower rate in the first half of the twentieth century, followed by much faster growth (worobey et al., ) . on a much shorter time scale, the bayesian skyline plot analysis of a dataset collected from a pair of hiv- donor and recipient was used to reveal a substantial loss of genetic diversity following virus transmission (edwards et al., ) . further analysis with a constant-logistic growth model estimated that more than % of the genetic diversity of hiv- present in the donor is lost during horizontal transmission. this has important implications as the process underlying the bottleneck determines the viral fitness in the recipient host. one disadvantage of the bayesian skyline plot is that the number of changes in the population size has to be specified by the user a priori and the appropriate number is seldom known. one solution is provided by methods that perform bayesian model averaging on the demographic model utilizing either reversible jump mcmc (opgen-rhein et al., ) or bayesian variable selection (heled and drummond, ) , and in which case the number of population size changes is a random variable estimated as part of the model. the methods for demographic inference discussed so far assume no subdivision within the population of interest. like changes in the size, population structure can also have an effect on the pattern of the coalescent interval sizes, and thus the reliability of results can be questioned when population structure exists ). in the next section we will discuss approaches to phylogeographic inference, including coalescent approaches to population structure. phylogeography is a field that studies the evolution and dispersal process that has given rise to the observed spatial distribution of population or taxa. phylogeographic methods can be divided into two approaches. the first performs post-tree-reconstruction analysis to answer phylogeographic questions, while the second jointly estimates the phylogeny and phylogeographic parameters of interest. when treating geographic location as discrete states, the former approach has been popular in the past couple of decades. it has the advantage of being less computationally intensive, but the outcome of the analysis depends on the input tree. due to its simplicity, the most popular method for inferring ancestral locations has been maximum parsimony (slatkin and maddison, ; swofford, ; maddison and maddison, ; wallace et al., ) , however this method does not allow for any probabilistic assessment of the uncertainty associated with the reconstruction of ancestral locations. a mugration model is a mutation model used to analyze a migration process. a recent study of influenza a h n virus introduced a fully probabilistic 'mugration' approach by modeling the process of geographic movement of viral lineages via a continuous time markov process where the state space consists of the locations from which the sequences have been sampled (lemey et al., b ). this fig. . the underlying wright-fisher population and serially-sampled genealogies from two populations. the first population has a constant population size over the history of the genealogy, while the second population has been exponentially growing. the coalescent likelihood calculates the probability of a genealogy given a particular background population history (e.g., constant or exponentially growing) and can therefore be employed to estimate the population history that best reflects the shape of the co-estimated phylogeny. facilitates the estimation of migration rates between pairs of locations. furthermore, the method estimates ancestral locations for internal nodes in the tree and employs bayesian variable selection (bvs) to infer the dominant migration routes and provide model averaging over uncertainty in the connectivity between different locations (or host populations). this method has helped with the investigation of the influenza a h n origin and the paths of its global spread, and also the reconstruction of the initial spread of the novel h n human influenza a pandemic (lemey et al., b) . however, a shared limitation of models for discrete location states is that ancestral locations are limited to sampled locations. as demonstrated by the analysis of the data set on rabies in dogs in west and central africa, absence of sequences sampled close to the root can hinder the accurate estimation of viral geographic origins (lemey et al., b) . phylogeographic estimation is therefore improved by increasing both the spatial density and the temporal depth of sampling. however, dense geographic sampling leads to large phylogenies and computationally intensive analyses. the structured coalescent (hudson, ) can also be employed to study phylogeography. the structured coalescent has also been extended to heterochronous data (ewing et al., ) , thus allowing the estimation of migration rates between demes in calendar units. the serial structured coalescent was first applied to an hiv dataset with two demes to study the dynamics of subpopulations within a patient (ewing et al., ) , but the same type of inference can be made at the level of the host population. further development of the model allowed for the number of demes to change over time (ewing and rodrigo, a) . migrate (beerli and felsenstein, ) also employs the structured coalescent to estimate subpopulation sizes and migration rates in both bayesian and maximum likelihood frameworks and has recently been used to investigate spatial characteristics of viral epidemics (bedford et al., ) . additionally, some studies have focused on the effect of ghost demes (beerli, ; ewing and rodrigo, b) , however no models explicitly incorporating population structure, heterochronous samples and nonparametric population size history are yet available. one ad hoc solution involves modeling the migration process along the tree in a way that is conditionally independent of the population sizes estimated by the skyline plot (lemey et al., a) . thus, given the tree, the migration process is considered independent of the coalescent prior. however this approach does not capture the interaction between migration and coalescence that is implicit in the structured coalescent, since coalescence rates should depend on the population size of the deme the lineages are in. as we will see in the following section, statistical phylogeography is one area where the unification of phylogenetic and mathematical epidemiological models looks very promising. in some cases it is more appropriate to model the spatial aspect of the samples as a continuous variable. the phylogeography of wildlife host populations have often been modeled in a spatial continuum by using diffusion models, since viral spread and host movement tend to be poorly modeled by a small number of discrete demes. one example is the expansion of geographic range in eastern united states of the raccoon-specific rabies virus (biek et al., ; lemey et al., ) . brownian diffusion, via the comparative method (felsenstein, ; harvey and pagel, ) , has also been utilized to model the phylogeography of feline immunodeficiency virus collected from the cougar (puma concolor) population around western montana. the resulting phylogeographic reconstruction was used as proxy for the host demographic history and population structure, due to the predominantly vertical transmission of the virus (biek et al., ) . however, one of the assumptions of brownian diffusion is rate homogeneity on all branches. this assumption can be relaxed by extending the concept of relaxed clock models to the diffusion process . simulations show that the relaxed diffusion model has better coverage and statistical efficiency over brownian diffusion when the underlying process of spatial movement resembles an over-dispersed random walk. like their mugration model counterparts, these models ignore the interaction of population density and geographic spread in shaping the sample genealogy. however there has been progress in the development of mathematical theory that extends the coalescent framework to a spatial continuum (barton et al., (barton et al., , a , although no methods have yet been developed providing inference under these models. box : the anatomy of a bayesian coalescent analysis using mcmc bayesian phylogenetic inference by markov chain monte carlo (mcmc) (yang and rannala, ; mau et al., ) involves the simulation of the joint posterior distribution of substitution model parameters (/) and the phylogenetic tree given the sequence data (d). by restricting the phylogenetic model to time-trees (see fig. ) and coupling the phylogenetic likelihood with a coalescent prior, the parameters (h) of the population history, n h (t), can also be estimated simultaneously by sampling from the posterior probability distribution (drummond et al., ) : the term pr(djg,/) is often referred to as the phylogenetic likelihood, and is the probability of the data given the time-tree g and substitution model parameters. it can be computed by the pruning algorithm (felsenstein, ) , which efficiently sums over all ancestral sequence states at the internal nodes of the tree. an extension of the likelihood accommodates heterogeneity across sites (yang, ) . if the time-tree g relates a heterochronous sample of sequences, then the substitution parameters / also includes the overall substitution rate l, and this can be estimated from the heterochronous data, so that the population history is estimated on a calendar scale. the normalizing constant pr(d) is also known as the partition function or marginal likelihood and its magnitude provides a measure of model support, although its estimation requires advanced mcmc techniques (e.g., thermodynamic integration or transdimensional mcmc). coalescent models come into play when determining the prior density for the time-tree topology and coalescent/ divergence times. the coalescent provides a probability distribution, f g (gjh), conditional on a deterministic model of population size history, n h (t). its parameters (h) can in turn be estimated as hyperparameters. given a time-tree g = {e g ,t} of n contemporaneous samples composed of an edge graph e g and coalescent times t = {t n = ,t nÀ , . . . ,t ,t } the coalescent density is: the prior distributions f h (h) and f u (/) are usually selected from standard univariate or multivariate distributions. in the previous section we have seen that phylogenetics can be used to infer the date of an outbreak, its source population and the viral transmission history, directly from time-stamped genomic data. whereas phylogenetic models mainly address questions about evolutionary history, dynamical models are often used to make predictions about the future. predictive models are important because they provide the possibility of anticipating certain aspects of the outcome of emerging epidemics and assessing the risk of pandemics, and the potential effects of planned intervention. phylogenetic inference is based on genetic data such as sampled dna sequences from infected hosts. current models using such data to infer information about the past often require simplifying assumptions about the population size e.g., to be constant or to be subject to pure exponential growth. epidemiologists, on the other hand, fit their models to prevalence or incidence data. standard epidemiological models are described by sets of ordinary differential equations tracking the (often non-linear) changes in numbers of susceptible and infected individuals. consequently, the simple prior assumptions for the population sizes (of infected individuals) used in phylogenetics appear inadequate from an ecological perspective. epidemiological models play a major role in deciding which measures of disease control are taken to avoid or stop viral outbreaks. the effects of isolation, vaccination and other measures are estimated through model simulations, serving as a basis for decisions on which public health policies to institute and actions to take. however, knowledge of the phylogenetic history of viral outbreaks can be vital in reconstructing transmission pathways which contributes to effective management and future prevention efforts (e.g., cottam et al., ) . the epidemiological and ecological processes determining the diversity of fast evolving rna viruses act on the same time scale as that on which mutations arise and are fixed in the population (holmes, ) . this implies that genetic sequence data can provide independent evidence on transmission histories. whereas epidemiological data typically provides information about who was infected and when, it generally does not provide positive evidence about transmission history. thus the combination of these sources of information should open the way to more detailed epidemiological inference, including bayesian estimation of contact networks and transmission histories (welch et al., ) . standard epidemiological models are based on flux between host compartments dividing the host population e.g., into susceptible (s), infected (i) and recovered or removed (r) individuals. standard models are termed si, sis and sir. the choice of model is based on the characteristics of the considered disease, the existence of a latent period, immunity after infection et cetera (see box ) (anderson and may, ; keeling and rohani, ) . restricting the focus to the time evolution of the number of individuals in each compartment, these models grasp the overall progress of an epidemic. certain disease characteristics require adaptations or extensions of standard models, for example, the inclusion of asymptomatic infections that account for a sampling bias towards symptomatic infections in case the virus of interest does not always cause noticeable symptoms (e.g., aguas et al., ) . an important threshold ratio is the basic reproduction ratio r , the expected number of secondary infections caused by one primary infection in a completely susceptible population (diekmann et al., ) . based on its value epidemiologists make predictions on the effect of the disease. in classical deterministic epidemiological models, if the basic reproduction ratio is larger than one, an epidemic is expected. box : compartmental models for infectious diseases (keeling and rohani, ) let s, e, i and r be the fractions of susceptible, exposed, infected and recovered/removed individuals in the host population. the left hand side of each equation block gives the model equations, the right hand side the (non-trivial) endemic equilibria, which are only obtainable for r > . the basic reproduction ratio r depends on the corresponding model. apart from the si model, the overall population is assumed to be constant, such that the sum of fractions for each model equals one. under the assumption of homogeneous mixing in the population the transmission term bs i can be derived, which determines the total rate of new infections. si model. fatal infections, eventually killing the infected, can be modeled with only two compartments: susceptible and infected. assume a fixed birth rate m and death rate l. the sir model. transmission of the disease to susceptibles leads to a period of illness until recovery, which in turn implies immunity. demography is described by the birth and death rate l and recovery is obtained at rate c; its reciprocal /c is the mean infectious period. here, r ¼ b lþc . the last equation is redundant since s + i + r = . instead, after infection the individuals go back to the susceptible stage. therefore, the disease can persist even without including newborns in the population. ignoring demography, the dynamics are characterized by coupled differential equations _ s ¼ ci À bsi and _ i = bs i À ci. since s = À i, they can be replaced by one equation. seir model. in order to account for a latent period with assumed average duration /r, the sir model can be extended by including exposed individuals composing a fraction e of the population. exposed individuals are infected, but not yet infectious. the differential equations for s (and r) are as in the sir model. dynamics in e and i are described as follows. further models are sirs, seis, msir, mseir, mseirs, etc., where m denotes passively immune infants, allowing for diseases where an individual can be born with a passive immunity from its mother. typically, epidemiologists fit a suitable set of deterministic differential equations to empirical data, often the number of infections or related hospitalizations in a population. consequently, the model can be used to estimate if an epidemic can be kept under control by measures such as (i) vaccination and (ii) antiviral prophylaxis for susceptible individuals, (iii) treatment of infected individuals or (iv) isolation of infected individuals from susceptible individuals. decisions on public health policies are often based on these estimates. the simplest epidemiological models assume homogeneous mixing within a population. in many cases this assumption is not valid. due to host contact dynamics viral infections spread easily within social units such as schools, cities and farms, less so among them. integration of population structure is therefore essential. however, even within subpopulations individual dynamics might differ stochastically (see fig. ). such randomness can be accounted for by considering stochastic models (see e.g., survey by britton, ) . before introducing stochastic compartmental models thoroughly, we illustrate them based on a stochastic sir model simulation. we simulate the spread of a virus strain in a population divided into n subpopulations which are connected by comparatively rare migration events. let l ¼ f ; . . . ; n À g denote the set of locations. a single infected individual initiates the epidemic in one of the n completely susceptible populations. after an exponentially distributed waiting time one of the following events happens: infection at mass action infection rate b. migration at migration rate m ik for ik l. birth of a susceptible individual at rate l. death of an individual at rate l. fig. shows a realization of the simulated dynamics for n = populations. the epidemic starts in population (blue) and many individuals get infected before the first individuals in population (yellow) and eventually population (red) get infected. let s k , i k and r k be the fractions of individuals in each subpopulation k l. the sum s k + i k + r k equals one for every k l. the deterministic analogue of our model can be described with the following differential equations: however it is important to realize that this set of differential equations cannot capture all of the behaviors of its stochastic counterpart. in fact, starting from a deterministic representation like this, there are multiple stochastic markov processes that exhibit the same deterministic limit, but can potentially have exponentially different behavior in their stochastic properties, such as the time to extinction (e.g., . formally, two distinct sources of variance can be considered in stochastic models of populations (engen et al., ) . the first is environmental stochasticity and is often modeled by admitting temporal variation in the parameters of the population model. the second is demographic stochasticity and describes the stochasticity of fluctuations in populations of finite size due to the inherent unpredictability of individual outcomes. to model demographic stochasticity (also known as internal stochasticity; chen and bokka, ) in the absence of environmental (external) stochasticity, the time-evolution of an epidemic can be represented by a jump process and its corresponding master equation (gardiner, ). the master equation describes the time evolution of the probability distribution over the discrete state space. for the closed sir model (kermack and mckendrick, ) the master equation for the numbers of individuals in each of the three compartments (n s , n i , n r ) is: _ p n s ;n i ;n r ðtÞ ¼ bðn s þ Þðn i À Þp n s þ ;n i À ;n r ðtÞ ð Þ þ cðn i þ Þp n s ;n i þ ;n r À ðtÞ À ðbn s n i þ cn i Þp n s ;n i ;n r ðtÞ a single realization of this epidemic jump process is described by a sequence of timed transition events (individual infection or recovery events). in the closed sir model, the waiting or sojourn time between a pair of sequential events is exponentially distributed (i.e., the transition process is memoryless), and thus the process is a continuous-time markov process. stochastic models of this form can also be viewed in terms of their reaction kinetics. for the closed stochastic sir model above the two 'reactions' are infection and recovery: indicating that a susceptible contacts an infectious individual and gets infected at reaction rate b whereas an infected recovers at reaction rate c. more precisely, the time (s) an individual spends in the susceptible and infected compartments are exponentially distributed with rates bi and c, respectively. it is the binary infection reaction that leads to the non-linear dynamics of the system. for stochastic models r > does not necessarily imply an outbreak of the disease. instead, a higher basic reproduction ratio suggests a higher probability of an outbreak, but the precise relationship depends on the specific model considered and the initial condition. algorithms have been developed that allow exact and approximate simulation of coupled reactions such as the closed sir (bartlett, ; gillespie, gillespie, , ). fig. shows simulated viral outbreaks under a stochastic sir and sis model with r % . in a population divided into three distinct subpopulations. note that there is no outbreak in ( ) although r > . deterministic epidemic models can be derived from the underlying jump process, and can represent useful macroscopic laws of motion in the appropriate limit. however such approaches are not adequate for modeling systems in which small numbers of individuals are frequently involved. for a similar reason, it is awkward to reconcile large-limit deterministic models with the small sample genealogies that are obtained with molecular phylogenetic approaches. therefore, stochastic continuous-time discrete-state formulations of epidemic models may be more suited to forming connections between the two disciplines. the forward simulations of a stochastic epidemic model introduced with fig. demonstrate the relationship between epidemic models and genealogies. knowing the exact parameters and resulting dynamics throughout the simulated outbreak, we can build a full transmission history for the outbreak (which is not unique given only the time evolution of the number of infected individuals, since at each event the infected individuals involved are chosen randomly). an infection event in the forward simulation corresponds to a bifurcation in the transmission tree. restricting the full tree to a ''sample genealogy'' that only includes the individuals that were infectious at a specific sampling time yields very different results for different times during the outbreak, which underlines the importance of sampling methods (see e.g., stack et al., ) . as we can see in the simulations, virus transmission often depends on spatial structure. the interaction among humans living in the same city, for example, differs from among-city interaction, which is important whenever viral transmission exceeds city borders. there are many other social and spatial units this concept applies to: households, schools, or on a larger scale, regions, countries and continents. in fact, most phylogenetic and epidemiological studies model the dynamics of spatially distributed systems, albeit many of them ignore spatial structure for the sake of simplicity. durrett and levin demonstrate that models ignoring spatial structure yield qualitatively different results than spatial models (durrett and levin, ) . phylodynamics is a term used to describe a synthetic approach to the study of rapidly evolving infectious agents that considers the action (and interaction) of both evolutionary and ecological processes. the term phylodynamics was introduced by grenfell et al. ( ) to describe the ''melding of immunodynamics, epidemiology, and evolutionary biology'' that is required to analyse the interacting evolutionary and ecological processes especially of rapidly evolving viruses for which both processes have the same time scale. two distinct pursuits have been labeled phylodynamics by recent studies. the first relies on the idea that ecological processes and population dynamics can effectively be tracked by neutral genetic variation, such that past ecological and population events are ''imprinted'' in genetic variation within populations and can be reconstructed along with the reconstruction of evolutionary history. the idea is sound for truly neutral variation, but the compact genomes of rapidly evolving viruses are not simple recording devices. instead they are packed with functional information and mutations play an active role in population and ecological processes through the action of darwinian selection. hence, the more challenging second phylodynamic pursuit is the analysis of the inevitable interaction of evolutionary and ecological processes that requires the joint analysis of both. we will call the former pursuit phylogenetic epidemiology, and reserve the term phylodynamics for approaches that aspire to model the interaction of ecological and evolutionary processes. the effect of novel mutations on population dynamics through their interaction with the immune system or anti-viral drugs are examples of phylodynamics in this stricter sense. the focus of many studies aspiring to combine population genetic and epidemiological approaches is the basic reproduction ratio r , estimates of which are used to develop containment strategies for emerging pandemics. such estimates can be obtained from phylogenetic analysis, e.g., through estimating population growth rates . another popular way to infer population dynamic information from genomic data is the application of parametric and non-parametric coalescent models (strimmer and pybus, ; drummond et al., ; minin et al., ) . phylogenetic methods can be used to estimate r , which can then be used to investigate transmission patterns and the number of generations of transmission. depending on the distribution of the generation time (i.e., the duration of infectiousness) the relationship between r and the growth rate r of the population can be used to compute the basic reproduction number (wallinga and lipsitch, ) . little is known about generation time distributions, the usual approach is to fit the epidemic models to the observed data. wallinga and lipsitch list the resulting equations for r for exponential, normal, or delta distributions of generation time. they show that without knowledge of the generation time distribution an upper bound for the reproductive number can still be estimated. others obtain r estimates based on coalescent theory, as for example (rodrigo et al., ) who estimated it in vivo for hiv- . in a recent study on the influenza a (h n ) outbreak in both epidemiological and bayesian coalescent approaches for the computation of r were applied (fraser et al., ) . whereas the epidemic approaches gave estimates of . - . for r , the bayesian coalescent approach yielded a posterior median of . . all estimates are larger than one, correctly indicating that the virus spreads successfully, rather than dying out. however, an agedependent heterogeneous epidemic model best fits the data and results in an estimate of r = . . structures determining host interaction are often modeled as contact networks (welch et al., ) . the transmission of foot and mouth disease virus is highly dependent on the interaction among farms and the detection of infected farms is essential. a plausible approach is to consider each farm as an individual in a contact network. through phylogenetic analysis of consensus sequences (one sequence for each farm) contacts between farms can be traced in order to find infected but non-detected farms such that contacts between farms can be traced in order to find infected but non-detected farms (cottam et al., ) . changes in effective population size estimated through phylogenetic analyses can indicate past changes in population size. therefore, many recent studies infer the demographic history of a virus using bayesian skyline plot models (drummond et al., ) . for example, (siebenga et al., ) are interested in the epidemic expansion of norovirus gii. which they investigate by reconstructing the changes in population structure using bayesian skyline plots. similarly, (hughes et al., ) explore the heterosexual hiv epidemic in the uk. analyses of the genomic and epidemiological dynamics of human influenza a virus explore the sink-source theory and investigate the spatial connections of a seasonal global epidemic (rambaut et al., ; lemey et al., b; bedford et al., ) . coalescent theory has also been adapted to fit an epidemic sir model to sequence data (volz et al., ). frost and volz ( ) provide an overview on how appropriate interpretation of coalescent rates differs among the different population dynamic approaches it is being used with. interpretation of the coalescent-based skyline plots must be made with caution. as opposed to generation times referring to durations of infection in epidemiological theory, for coalescent approaches being applied to infectious diseases the generation times usually describe times between transmission events. accordingly, although prevalence does affect phylogenetic reconstruction through sampling, the population dynamic patterns are mainly determined by incidence (frost and volz, ) . one early attempt to integrate dynamical and population genetic models used coupled differential equations and markov chain theory to model the within-host time evolution of viral genetic diversity under basic dynamic models of a persistent infection (kelly et al., ) . the main focus was the impact of the dynamical model on the variance in the number of replication cycles, as this is a key determinant of the rate of genetic divergence and thus potential for adaptation. interestingly, the model reveals that multiple cell type infections can decrease viral evolutionary rates and increase the likelihood of persistent infection. genetic diversity within hosts is closely related to between host dynamics: gordo and campos ( ) develop structured population genetic models, explicitly incorporating epidemiological parameters to analyze the relationship between genetic variability and epidemiological factors. a simple sis model is simulated based on two different models of host contact structure, the island model and a scale free contact network. for low clearance rates and low intrahost effective population size, levels of genetic variability turn out to be maximal when transmission levels are intermediate, independent of the host population structure. in a scale free contact network the population consists of many low-connectivity hosts and very few high-connectivity hosts, a common pattern for sexually transmitted diseases (e.g., lloyd and may, ; liljeros et al., ) . in this setting genetic variation appears to be lower in highly connected than in weakly connected hosts. with their study gordo and campos ( ) underline that an integration of population genetics and epidemiology can have important implications for public health policies. in a deterministic framework day and gandon ( ) model the interaction of evolutionary and ecological processes by coupling sis host dynamics with viral evolution. the interaction of evolution and ecology is incorporated through the fitness of each virus strain. for strain i they define a fitness r i = b i n s À l À v i À c, where b i is the strain-specific transmission rate per susceptible, v i is the strainspecific virulence (determining the increase in mortality rate due to infection), l is the baseline mortality rate and c is the recovery rate. the evolutionary dynamics of strain frequencies are tracked quantitatively and the evolutionary dynamics of strain frequencies are intimately linked with the overall infection dynamics of the host population via the strain-specific virulence and transmission rates. their analysis provides insight into the mechanistic laws of motion connecting genetic evolution with the evolution of virulence and transmission rates. an exceptional feature of influenza viruses is the limited genetic diversity which appears to contradict the viruses' high mutation rate. integrating single virus strain features and host immunity into a stochastic transmission model ferguson et al. ( ) search an explanation for this. although epidemiological factors play a role in limiting influenza diversity, strain-transcendent immunity must be relevant as well. through a phylodynamic analysis of interpandemic influenza in humans koelle et al. ( ) underline the importance of the viral structure for antigenicity and the immune recognition dynamics of influenza epitopes. they consider clusters that contain strains with similar conformations of ha epitopes such that there is high cross-immunity of strains within each cluster. a genotype-phenotype model that implements neutral networks (the clusters) is coupled with an epidemiological transmission model in which the number of susceptible, infected and recovered individuals in each cluster are modeled. model simulations result in time series of infected cases that agree with the typical annual outbreaks in temperate regions and empirical dominance of certain antigenic clusters. according to this model, years in which a formerly dominant cluster is replaced by a new one have the highest numbers of infections. in the following year there are particularly few infec-( ) ( ) ( ) fig. . simulated viral outbreak under stochastic sir ( - ) and sis ( ) model among three populations (denoted by blue, yellow and red curves). the initial condition is a single infected individual in the blue population. in ( ) the disease does not break out (numbers of susceptibles in dotted lines and infected in solid lines). (for interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) tions, presumably due to higher host immunity caused by the previous year's outbreak. thereafter follow ''average'' years until the next cluster-transition occurs, i.e., until another cluster becomes dominant again. another natural explanation of the contradiction between high mutation rates and constant genetic diversity is the fixation of many deleterious mutations that leads to the extinction of the respective strains. recent population genetic models account for population dynamics e.g., in order to enhance the understanding of allele fixation processes and the importance of demographic stochasticity (parsons and quince, ; champagnat and lambert, ; parsons et al., ) . structured models do not only allow for more realistic dynamics, they can also bridge the gap to phylogenetic/-geographic methods since most of them are sample-based, ideally, with each sample representing one infected individual. modeling coupled host-virus dynamics welch et al. ( ) embed an epidemic population model into a branching and coalescent structure, producing a scaled coalescent process that describes the inter-host dynamics given a virus sample genealogy. their simulations show that, for large sample sizes, the model provides accurate estimates of the contact rate and the selection parameter. overall, phylodynamic methods have been developed and proven useful for the analysis of various viruses. however, phylogenetic reconstruction is still quite restricted by coalescent assumptions. an alternative to the coalescent for cases in which sample sizes are big compared to the overall population is the birth-death with incomplete-sampling model (gernhard, ; stadler, ) , and this framework has recently been extended to include heterochronous data (stadler, ) , opening the way for an alternative approach to phylodynamic inference from timestamped virus data. bayesian phylogenetic inference has led to an explosion of analyses of rapidly evolving viruses in recent years. while this explosion has been fruitful in elucidating the manifold variation in origin, transmission routes and evolutionary rates underlying the present diversity of infection agents, there is a nascent field that promises to extend the conceptual reach of molecular sequence data, through a unification of phylogenetics and mathematical epidemiology. this new field of phylodynamics encompasses both inference of classical epidemiological parameters using phylogenetics as well as exciting new approaches that aim to investigate the consequences of the inevitable interaction between evolutionary (mutation, drift, darwinian selection) and ecological (population dynamics and ecological stochasticity) processes. the research being pursued has broader consequences for evolutionary biology and molecular ecology. this interaction of evolution and ecology will occur whenever a population contains genotypes with different intrinsic dynamical properties (e.g., virulence, transmission 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history of siv evolution in mendelian populations maximum likelihood phylogenetic estimation from dna sequences with variable rates over sites: approximate methods bayesian phylogenetic inference using dna sequences: a markov chain monte carlo method historical perspective-emergence of influenza a (h n ) viruses key: cord- -iqr fp authors: fan, changyu; liu, linping; guo, wei; yang, anuo; ye, chenchen; jilili, maitixirepu; ren, meina; xu, peng; long, hexing; wang, yufan title: prediction of epidemic spread of the novel coronavirus driven by spring festival transportation in china: a population-based study date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: iqr fp after the novel coronavirus ( -ncov) outbreak, we estimated the distribution and scale of more than million migrants residing in wuhan after they returned to their hometown communities in hubei province or other provinces at the end of by using the data from the – china migrants dynamic survey (cmds). we found that the distribution of wuhan’s migrants is centred in hubei province (approximately %) at a provincial level, gradually decreasing in the surrounding provinces in layers, with obvious spatial characteristics of circle layers and echelons. the scale of wuhan’s migrants, whose origins in hubei province give rise to a gradient reduction from east to west within the province, and account for % of wuhan’s total migrants, are from the surrounding prefectural-level cities of wuhan. the distribution comprises districts and counties in hubei province, and the cumulative percentage of the top districts and counties exceeds %. wuhan’s migrants have a large proportion of middle-aged and high-risk individuals. their social characteristics include nuclear family migration ( %), migration with families of – members ( %), a rural household registration ( %), and working or doing business ( %) as the main reason for migration. using a quasi-experimental analysis framework, we found that the size of wuhan’s migrants was highly correlated with the daily number of confirmed cases. furthermore, we compared the epidemic situation in different regions and found that the number of confirmed cases in some provinces and cities in hubei province may be underestimated, while the epidemic situation in some regions has increased rapidly. the results are conducive to monitoring the epidemic prevention and control in various regions. the outbreak of a new coronavirus ( -ncov) has spread internationally since the initial report of cases by wuhan municipal health commission, china on december [ ] [ ] [ ] [ ] . on january , who announced that there is a high risk of a -ncov epidemic in china and at a global level [ ] . the analysis object of this study was the floating population who have lived in wuhan for more than one month. short-term migrants and students were not included. distinct from other models of the dynamics of this epidemic, we used the information of the respondents from the cmds and their family members to further explore the origins of wuhan's migrant population, such as their returning destination, population characteristics, family structures and other metrics. this approach can provide practical solutions to prepare prevention strategies, and approaches to assess resources for treatment and containment of the epidemic. the national health commission of china released a report on january that stated that -ncov could be transmitted not only via respiratory droplets, but also via direct contact. -ncov has now spread nationally and worldwide, and due to the lack of data on the size and origins of the floating population of wuhan, it has been difficult for the chinese government to arrange real-time medical resources and implement effective public health interventions. we used data from the wuhan floating population monitoring survey to estimate the size and origins of the migrant population in wuhan. we also described the socio-demographic characteristics of this population, and compared confirmed cases from different regions to estimate the epidemic with modelling techniques. we found that three-quarters of wuhan's floating population are from hubei province, and that nearly % migrated with nuclear families. the number of members per family is to , and most individuals are migrant workers from rural areas with low education levels. by comparing the predicted and actual values obtained from the model, we analysed the profile of the epidemic in various regions since january , and found that the spread of the -ncov has varied greatly between regions, and that the epidemic in some regions may be underestimated. there may also be unknowns, such as structural factors in some regions, that deserve further attention. the majority of the floating population left wuhan before the city was "closed off" by authorities, so our analysis will be useful for estimating the key geographic areas for prevention and control. the results indicate that the floating population of wuhan is centred in hubei province and the surrounding provinces, so local government must quickly and effectively take steps to prevent further spread of -ncov. higher-level governments must also strengthen the assistance they are providing, such as sending medical workers and medical supplies to these areas to avoid -ncov becoming a new pandemic. at the same time, it is important to increase surveillance in areas where the epidemic may be underestimated, and promptly identify prevention and control loopholes to reduce the burden of a new round of transmission. china has been deeply involved in the globalisation process, and even china's central and western regions have become important links in the global production and trade chain. therefore, while our research is aimed at china in the current era of migration, this research has practical implications for global public health and disease control, as floating populations are increasing in size all over the world and relationships between countries are becoming increasingly close. thus, other countries should pay attention to the epidemic situation in specific geographic areas of china to prevent secondary and international transmission of the -ncov. the data used in this study are based on the - china migrants dynamic survey (cmds), and the tabulated data of million migrants in wuhan recently released by the wuhan municipal government. this survey was carried out via a multi-stage stratified sampling method, and collected data with structured questionnaires. as survey data is limited to the mainland provinces, municipalities, autonomous regions, and hainan province, the population analysed in this study excluded the populations of hong kong and macao. a total of , samples of the resident floating population in wuhan from to were extracted from the survey dataset. according to the survey design, wuhan's floating population was defined as the population from other cities and districts, aged and over, residing for more than one month in wuhan, and not registered in wuhan. in table , the sample distribution of the resident population in wuhan over time is presented. the sample size was in the year , and for other years. the outbreak is considered to have originated in the huanan seafood market, near hankou railway station in the jianghan district, wuhan, china. a severely infected area was concentrated in the urban areas of hankou. from the sample distribution in table , the floating population of wuhan is seen to be concentrated in the urban area of hankou. the results indicate that the sample proportion of jianghan district and nearby jiang'an district, tongkou district, and dongxihu district is approximately . %. therefore, the samples used in this study are suitably representative and thus acceptable for assessing the spread of the -ncov outbreak among the floating population. total , hankou zone jiang'an - qiaokou - jianghan - dongxihu - huangpi - xinzhou - wuchang zone hongshan - wuchang - qingshan - jiangxia - hanyang zone hanyang - hannan - caidian - all three zones ----- we obtained data from the "dingxiangyuan" national real-time epidemic website on confirmed cases from january to january [ ] . these data are compiled from open data released by authorities such as the national health commission, and the provincial and municipal health commissions. to ensure data comparability, we collected the data daily from : to : every day. using the information of the floating population and their family members in wuhan, we analysed their return destinations and their structural characteristics by descriptive statistical methods. in table , the distribution of the origins of wuhan's floating population is presented, at the provincial level, over the past several years. the sample size is quite stable for each province over time. the province of origin for % of the floating population was hubei province, which contains the city of wuhan, and approximately % of the population originated in other provinces. the location information published in other historical survey data is limited to the province where household registration is located, due to a lack of data for . the data provided by the hubei provincial health commission in includes more detailed information of prefectures, cities, districts and counties. the analysis was therefore divided into two parts; the first part comprised an analysis of the origin of wuhan's floating population at the provincial level using historical data. the second part comprised an analysis of the floating population within hubei province based on data. when analysing the floating population at the provincial level, we used all samples from the previous years-i.e., the mean of years of data collection-to ensure the robustness of the results, in view of the stability of sample distributions in each province over time. total , hubei henan anhui hunan jiangxi chongqing zhejiang sichuan fujian jiangsu shandong guangdong hebei tianjin shanghai inner mongolia xizang ningxia according to the current infectious features of -ncov, which are that middle-aged and elderly people have a high risk of infection, and transmission can occur between individuals, families and communities, we assessed several main variables. these comprised age group, educational level, pattern of migration, number of migrating family members per household, type of household registration, and reasons for migration. we defined these variables in the following ways: ( ) age group was classified as under , - , - , - , - , and over ; ( ) educational level was divided into junior high school and below, high school/secondary school, and college and above; ( ) pattern of migration was divided into independent migration, nuclear family migration, and extended family migration; ( ) number of migrating family members per household was classified as , , , , and or more; ( ) types of household registration were divided into rural and urban household registration; ( ) reasons for migration were working and doing business, family relocation, or other reasons. the analyses assume a theoretical model of -ncov transmission. we considered a floating population of million in wuhan, who returned to their hometowns from january , as potential infected persons. moreover, we added factors of demographic characteristics, the situation of medical diagnosis, government prevention and control, the number of confirmed cases, and undisclosed data to our statistical model to estimate the dynamics of the epidemic. after controlling for certain factors, we analysed the factors that were not controlled, such as government intervention and the number of statistical reports. specifically, we first analysed the correlation between the size of the floating population in wuhan and the number of confirmed cases per day. then, we examined the differences among regions and proposed a transmission rate as a reference to compare the differences in regions. in the comparative analysis, we focused on the probably underestimated number of cases and the virus transmission rate to determine the likelihood of epidemics existing in different regions. finally, we predicted the floating population of wuhan using statistical methods and compared it with the number of -ncov confirmed cases in each region, to identify regional differences of -ncov infection. furthermore, we predicted the forthcoming epidemic trend at the prefectureand province-level based on the proportion of wuhan's floating population represented by people from these areas. human-to-human transmission of the -ncov has been confirmed. four sets of factors that may influence regional differences appear to be involved: ( ) demographic factors, such as short-term business travellers between wuhan and other regions, college students in wuhan returning to their homes in other regions, spring festival tourists from wuhan to other regions, and trans-regional floating populations for spring festival family reunions from or across wuhan; ( ) intervention factors, such as medical treatments and governmental preventative measures; ( ) information disclosure and the information release system; and ( ) other unknown factors. we considered all these factors, and hypothesised the social environment of -ncov transmission. first, although the government had taken the unprecedented measure of sealing off wuhan city on january , we assumed that, at that time, the entire floating population of wuhan, all short-term business travellers to wuhan and all college students in wuhan had returned to their hometowns throughout china, because january was the spring festival's eve (normally, the spring festival holiday from january to ). moreover, this spring festival vacation period started at least a week before this date time, leaving plenty of time for these people to leave the city. however, the number of people in wuhan that travelled to reunite with their families in other cities during the spring festival vacation may be negligible, for the sealing-off of the city and other preventive measures taken across the country may have prevented their travelling. second, the influence of the college students in wuhan was an invariant factor, as college students are young and healthy, have fixed travelling routes, come from different regions evenly scattered across the country, and travelled to return home on or around january ; we would assume their influence on virus transmission to different regions to be the same. third, the medical treatment ability of regional medical centres of hubei province would also be the same, as the breakout emerged so fast that these regional medical centres would have had the same level of emergency-preparedness. finally, the above factors will not change dramatically until the mass return of wuhan's floating population after the conclusion of the spring festival vacation. to estimate the floating population in the cities of hubei province and across the country, we must determine the floating population residing in wuhan in . as the statistics compiled by the wuhan city government from have not been released, the data from previous years was used for this prediction. the prediction of floating population in wuhan based on the statistics from previous years is presented in table , demonstrating that there were approximately . million migrants living in wuhan for more than six months in . however, if the predictions of the statistical data were combined with survey data, which was used in this study to estimate the origin of wuhan's floating population that return to their hometowns, there would have been a problem with inconsistent statistical strength. this would have resulted from the fact that the floating population measured by the government statistics department reflects those who have lived in wuhan for more than months, but the respondents in the survey have lived in wuhan for over one month. a shorter defined residence time would have therefore produced a larger estimate of the population, and thus the total floating population in wuhan, as determined from the cmds data, was larger than the population as determined by the government statistics department. on january , xinhua news agency (an official government media source) interviewed the mayor of wuhan and reported that more than million members of the floating population had returned to their hometowns before the spring festival holiday. this number stated (over million) was more than twice the predicted value in this study ( . million), indicating that the statistical strength of the news report was based on a shorter period of residence, and this was consistent with the data we used to determine the floating population residing in wuhan for over one month. thus, in the absence of more rigorous and authoritative total data, we used million people as wuhan's floating population, from which to estimate the scale and distribution of those members of this population who returned to their hometown during the festival. based on sample survey data, in table , the proportional estimation of the origins of wuhan's floating population at a provincial level is presented, as well as the results of statistical analysis based on a floating population of million. estimation of population size is based on the total number of floating population in wuhan (about million); ci = confidence interval. the national distribution of the migrants presents obvious spatial characteristics of circle layers and echelons at provincial level (table and figure ). ( ) hubei province is the central area of origin of wuhan's floating population, accounting for % of the population, with a % confidence interval of ( . , . ). based on a total population of million people, wuhan's floating population with household registration in hubei province is approximately . million, with a % confidence interval of ( , , to , , ). ( ) henan, anhui, jiangxi and hunan provinces belong to the first circle layer. henan province, home to a floating population of , , had the highest proportion with respect to its total population, equating to approximately . % and a % confidence interval of ( , to , ). based on the analysis of city data in , xinyang, zhumadian, shangqiu, and nanyang cities in henan province accounted for . %, . %, . %, and . % respectively, of the floating population from henan living in wuhan, accounting for approximately % of the total. the floating population proportions of anhui, hunan, and jiangxi provinces were . %, . %, and . %, respectively, with corresponding floating populations in wuhan of , , , , and , respectively. ( ) chongqing, zhejiang, sichuan, fujian and jiangsu provinces are at the second circle layer, with . %, . %, . %, . % and . % floating populations, respectively, with corresponding populations of approximately , , , , , , , and , respectively. ( ) shandong, guangdong, hebei, gansu, guangxi, heilongjiang, shaanxi, shanxi and guizhou provinces are at the third circle layer, with a proportion of . % to . % and a corresponding population of , to , . ( ) some provinces and municipalities, including qinghai, liaoning, yunnan, jilin and beijing, are located in the fourth circle layer, accounting for . - . % of the floating population, equating to - people. ( ) the remaining provinces and municipalities, such as hainan, xinjiang, tianjin, shanghai, inner mongolia, tibet and ningxia, are at the fifth circle layer, with a floating population proportion of less than . %, corresponding to ≤ people. as presented in the table above, this population is mainly - years old, but the scale of the susceptible, high-risk and over years old population is also very large. the distribution is as follows: ( ) the susceptible and high-risk population is concentrated in hubei province. the size of the - age group is more than , , that of the age group of - is , , and the number of people over is , . ( ) henan and anhui provinces have larger susceptible and high-risk populations, of more than , and nearly , , respectively. ( ) six provinces and municipalities, namely hunan, jiangxi, chongqing, zhejiang, sichuan and jiangsu, have a high-risk population of to years old, comprising , - , people. ( ) in provinces, namely fujian, shandong, guangdong, hebei, gansu, guangxi, shanxi, guizhou, qinghai and xinjiang, the susceptible and high-risk populations are also concentrated in the - age group, with a population of approximately - . ( ) the three provinces of northeast china, namely heilongjiang, jilin and liaoning, have large susceptible and high-risk populations, equating to approximately in heilongjiang and approximately in jilin and liaoning. infection of family members is a main means of transmission, and the distribution of the characteristics of floating population family migration at the provincial level are detailed in table . the vast majority of the floating population migrates to wuhan in the form of nuclear families ( . %), and most families comprise - members ( . %). the distribution is as follows: ( ) the number of nuclear family households in the wuhan floating population that originates from hubei province is . million, accounting for . % of the total floating population of wuhan, and households with - family members number , , , accounting for . % of the total. the high risk of -ncov transmission within and by this population is self-evident. ( ) families from henan, anhui, hunan and jiangxi provinces comprise a large proportion of those in the floating population of wuhan. those from henan total nearly , households, and the number of these households with - family members is more than , . approximately , families from the remaining provinces are part of the floating population of wuhan, including nearly , - family-member households from anhui and more than , from hunan and jiangxi. ( ) the number of families in the floating population of wuhan from chongqing, zhejiang, sichuan, fujian and jiangsu municipalities and provinces is , - , , and the number of households with - family members is , - , . ( ) the number of families in the floating population of wuhan that originate from other provinces, namely shandong, guangdong, hebei, gansu, guangxi, heilongjiang and shaanxi, is , - , households, and the number of households with - family members is approximately , . the remaining provinces comprise fewer than , households jiangxi. certain factors can easily spread the virus from homes to communities in rural areas, such as a lack of medical resources and investment, weak health prevention and control, low awareness of health, and insufficient awareness of infectious diseases. in table , the floating population in wuhan is dominated by rural households ( . %), and working or doing business is the main reason for their having travelled to wuhan ( . %). therefore, epidemic prevention and control in rural areas is of critical importance. the distribution is as follows: ( ) the joint distribution of the origins of wuhan's floating population within hubei province is . %, equating to a population of , , , and . % of these are migrant workers, equating to , , people. ( ) henan, anhui, hunan, and jiangxi province both have more than , households with rural household registers and migrant workers in wuhan, and the population of those from henan in wuhan's floating population is approximately , . ( ) chongqing, zhejiang, sichuan, fujian, jiangsu, shandong, guangdong, hebei, gansu, and guangxi provinces together have a population of , - , households with rural household registers in wuhan and less than , in the remaining provinces of china. notably, guangdong, gansu, heilongjiang and liaoning have a larger proportion of the population with urban household registers, and this is greater than the number of rural household registers in guangdong province. , , guizhou qinghai liaoning yunnan beijing jilin hainan xinjiang tianjin shanghai inner mongolia xizang ningxia virus transmission is related to individual health awareness, which is affected by an individual's educational level, so we also examined the educational level of the floating population in wuhan. in table , % of the population was educated to junior middle school and below, % had senior high school or technical secondary school education, and % had college education and above, indicating that the overall education level of this population was low. specifically: ( ) in the provinces of qinghai, chongqing, jiangxi, anhui, henan, yunnan, guangxi and xinjiang, % or more of the population was educated to junior high school level or below. ( ) approximately - % of the population of the provinces of hubei, sichuan, hebei, fujian, jiangsu, hunan, guizhou, shandong, shanxi, tibet and gansu was educated to junior high school level or below. ( ) the population in three municipalities, including beijing, tianjin and shanghai, have a high level of education, with over % receiving tertiary education. the population of the remaining provinces had a medium-to-high educational level. above all, these data indicated that there is a large middle-aged and older high-risk floating population in wuhan. their social characteristics include having travelled to wuhan in a nuclear family of - members, being on a rural household register, and often having a lower educational level. these characteristics are consistent with conditions favouring the wide spread of -ncov. according to the foregoing analysis, % of wuhan's floating population have registered households in hubei province, equating to approximately . million people. that such a large proportion of the floating population of wuhan originate from elsewhere in hubei province has reduced the possibility of the epidemic spreading across the country, but all regions in hubei province are facing tremendous pressure from the spread of the epidemic. therefore, we used the cmds data to analyse the distribution of the floating population in regions within hubei province. table and figure present the distribution of the origins of wuhan's floating population within hubei province. the proportion of the floating population gradually decreases from east to west across hubei province, and there are great differences between cities. the distribution is as follows: ( ) xiaogan, wuhan, and huanggang are in the first echelon. the proportion of the floating population who originate from these cities is high, accounting for . %, . %, and % of the total, respectively. they are a cross-regional floating population of , and a % confidence interval of ( . , . ). the analysis of districts and counties indicates that the members the floating population who originate from the outskirts of huangpi district and xinzhou district flow into the main urban area of hankou, so the epidemic situation in the outskirts of huangpi district and xinzhou district needs special attention. secondly, the members of wuhan's floating population who originate from xiaogan comprise the largest proportion, equating to approximately , people and a % confidence interval of ( . , . ). members of wuhan's floating population who originate from huanggang comprise the third proportion, equating to approximately , people and a % confidence interval of ( . , . ). ( ) the three directly managed by province (dmp) cities (xiantao, qianjiang, and tianmen) and jingzhou belong to the second echelon, each comprising approximately , people, and each accounting for approximately % of the floating population of wuhan, with a % confidence interval of ( , ). ( ) jingmen, suizhou, xianning, and huangshi belong to the third echelon, accounting for - % of the floating population of wuhan, equating to , - , people. ( ) xiangyang, ezhou, yichang, enshi, and shiyan belong to the fourth echelon, accounting for less than % of the floating population of wuhan, equating to fewer than , people. overall, the suburbs of wuhan surrounding xiaogan, huanggang, and the three dmp cities are the origins of the largest proportion ( %) of the floating population of wuhan, equating to approximately . million people. we used district-and county-level variables to estimate the floating population within hubei province, and the results are presented in table . the survey covered districts and counties, including huangpi, xinzhou, jiangxia, caidian, and hannan in wuhan, as well as cross-region active migrants in some major urban areas. the top districts and counties of hubei province in terms of floating population are huangpi, hanchuan, xiantao, xinzhou, hong'an, yunmeng, honghu, macheng, xiaonan, and xiaochang. that is, ≥ , people from each of these districts and counties are part of the floating population of wuhan, with the top districts and counties, huangpi, hanchuan and xiantao, having ≥ , people in wuhan's floating population. these top district and counties of hubei province are followed by jingshan, yingcheng, dawu, guangshui, tianmen, lishui, jianli, anlu, jiangxia and caidian, which each have , - , people in wuhan's floating population. the third tier is huangmei, yangxin, daye, gongan, tongshan, jiayu, zhongxiang, qianjiang, songzi, huarong, zengdu, enshi, liangzihu, zaoyang, dongxihu, wuxue, huangzhou, hannan, xian'an, xiangzhou, zhijiang, echeng, luotian, badong, chibi, chongyang, hongshan, shayang, shishou, suixian, tuanfeng, gucheng and xiangcheng. these districts and counties each have , - , people in wuhan's floating population. the remaining districts and counties have fewer than , people in wuhan's floating population. in general, these members of wuhan's floating population originate from certain districts and counties of hubei province. the cumulative percentage of the top districts and counties exceeds % of these areas' total population, showing a clear exponential distribution trend. we then analysed the social characteristics of the migrants in hubei province by age, type of migration, number of migrants, type of household registration, and reasons for traveling to wuhan to become part of its floating population. from table (please see the last page), we observe that in terms of susceptible and high-risk groups over years old, there are approximately , people in xiaogan, approximately , people in wuhan (cross-region migration), and approximately , people in huanggang. there are also approximately , people in the dmp cities and jingzhou respectively, and , - , people in jingmen, suizhou, xianning, and huangshi. fewer than , people from each of xiangyang, ezhou, yichang, enshi and shiyan have travelled to wuhan. the migration characteristics of the floating population of wuhan from hubei province are detailed in table . migration with a nuclear family is the main pattern, accounting for nearly % of the total, or . million households. the proportion of households with - family members (i.e., nuclear families) is approximately %, or . million households. specifically, , nuclear families originate from xiaogan, , - , nuclear families originate from the inner suburbs of wuhan and huanggang, and approximately , nuclear families originate from the dmp cities and jingzhou. more than , nuclear families originate from jingmen, suizhou, xianning, and huangshi, while fewer than , nuclear families originate from xiangyang, ezhou, yichang, enshi and shiyan. the distribution of households with - members is similar to that of nuclear families. it also presents the distribution of the origins of wuhan's floating population who originate from within hubei province. according to the statistical results, rural household registers account for %, equating to a population of approximately . million. the proportion of the group who was working and doing business in urban areas is %, and the population is . million. the size of the population distribution in each city is similar to the aforementioned migration types and other variables, and is not reported here. in table , the overall educational level of those members of wuhan's floating population who originate from hubei province is higher than the national level, with approximately % having been educated to junior high school level and below, approximately % to high school/secondary school level and below, and approximately % to college and above. however, in those members of wuhan's floating population who originate from the surrounding cities of wuhan, which contribute a large number of people to the floating population of wuhan, namely xiaogan, huanggang, huangshi, suizhou, dmp cities, xianning, and ezhou, > % of people have an educational level of junior high school and below, with this being > % in xiaogan. this means that the awareness of health protection and timely treatment may be low in this section of the floating population of wuhan, which will heighten the risk of large-scale transmission of -ncov. the floating population in wuhan will serve as a sound predictor for the trend of the -ncov outbreak. the pearson's correlation coefficient between the proportion of the floating population in wuhan who originate from a certain region of hubei and the number of confirmed -ncov cases in each region increased from . on january to . on january (table ). this indicates that when a region contributes a higher number of people to the floating residential population of wuhan, more confirmed cases will emerge in this region. table ); ratio = confirmed cases (on / / )/floating population from wuhan (unit: , people); dmp (directly managed by the province) cities includes xiantao, qianjiang and tianmen; the pearson's correlation coefficient is calculated from the number of floating populations in wuhan and the number of confirmed cases per day. we assumed that the effect of the floating population on the transmission of the -ncov is consistent across hubei province, and selected three prefectures that contribute the greatest number of people to the floating population of wuhan (xiaogan, huanggang and jingmeng) as the reference prefectures to predict the epidemic trend of the -ncov at prefecture level. those prefectures can be divided into three groups since january ( the floating population of wuhan originated from outside hubei province may have promoted the spread of -ncov. table compares the number of individuals travelling from wuhan to other provinces and the daily number of confirmed cases for those other provinces. analysis revealed that the correlation coefficient at the provincial level was lower than at the prefecture level within hubei province, but the correlation coefficient increased from . on january to . on january . table also shows the ratio of confirmed cases in each province to the proportion of people in the floating population in wuhan who originate from each of these provinces, on january . we divide provinces into two categories based on their short-term travel populations in wuhan, and wuhan's travelling population to other provinces during the spring festival holiday. the first category comprises those provinces that have large-scale short-term business trips or tourist populations in wuhan during the spring festival holiday, namely beijing, shanghai, tianjin, and hainan. obviously, such a high level of inter-provincial population mobility may exacerbate the spread of -ncov. for example, the high ratio of confirmed cases in guangdong province may be due to the large short-term travel populations visiting shenzhen and guangzhou and wuhan, while the high ratio of confirmed cases in hainan province may result from the outbound tourist population from wuhan to hainan during the spring festival holiday. in table , the results are divided into two parts: the correlation coefficient of the first category of provinces, which reaches a maximum of . , and the correlation coefficient of the second category of provinces, which increased from . to . . this abovementioned second category comprise the other provinces that have small short-term business trip groups or tourist populations in wuhan during the spring festival holiday. we assumed that the effect of the floating population on the spread of -ncov was consistent across the country. the other provinces are divided into three groups since january ( figure ) : ( ) provinces with a rapid increase in the number of confirmed cases, namely zhejiang, shandong, guangxi, shaanxi, liaoning, and yunnan; ( ) provinces with a moderate increase in the number of confirmed cases, namely hunan, chongqing, sichuan, fujian, jiangsu, hebei, gansu, heilongjiang, shaanxi, guizhou, qinghai, jilin, xinjiang, inner mongolia, tibet, and ningxia; and ( ) provinces with a small increase in the number of confirmed cases, namely henan, anhui, and jiangxi. in table , if we exclude the data of henan province and zhejiang province from the second category, we find that the correlation coefficient on january is . . we selected four provinces (henan, hunan, sichuan, and zhejiang) as the reference provinces to predict the epidemic trend of -ncov in each province. we found that: ( ) the epidemic growth model of henan province does not fit the situation in most other provinces. that is, except in anhui and jiangxi, the actual number of outbreaks in other provinces was higher than that predicted by the henan model. as these provinces have large floating populations in wuhan, the rapid increase in the number of confirmed cases in henan, anhui and jiangxi may result from effective measures that have been taken to control the spread of -ncov, or the lack of sufficient diagnostic capabilities to detect suspected cases. ( ) the epidemic growth model for hunan and sichuan province predicts a rapid increase in the number of confirmed cases in henan, anhui and jiangxi provinces. thus, if the epidemic pattern in hunan and sichuan follows a typical evolutionary pattern, the current numbers of confirmed cases in the three provinces of henan, anhui, and jiangxi are greatly underestimated. for example, the number of confirmed cases in henan on january would be between and , but the number in official announcements was only . in contrast, the number of confirmed cases in zhejiang, shandong, guangxi, shaanxi, liaoning, and yunnan provinces were higher than the predicted number, which may be affected by uncontrollable local factors that need further investigation. ( ) the epidemic growth model for zhejiang province predicts a rapid increase in the number of confirmed cases in most provinces, especially jiangsu and fujian provinces that are adjacent to zhejiang. it is important to investigate why there were so many confirmed cases in zhejiang, and whether the outbreak in jiangsu and fujian province was not detected in a timely manner, or whether all possible cases have not yet occurred. overall, the predicted epidemic pattern for hunan and sichuan provinces fits best to the actual epidemic trend of the -ncov outbreak. however, the current number of confirmed cases in henan, anhui, and jiangxi provinces is likely to be underestimated, especially given that these contain extensive rural areas with large populations and limited medical resources. the higher actual number of confirmed cases in zhejiang, shandong, guangxi, shaanxi, liaoning, and yunnan provinces may be affected by other unknown factors or uncontrollable random factors that need further investigation. to prevent or mitigate the spread of an emerging infectious disease and its negative effects, public health interventions mainly aim at three types of population, namely the population in the source area, the floating population leaving the source area, and the population travelling from the infected area to other areas. the spring festival in is much earlier than in previous years. at this time, the possibility of human-to-human transmission of a new coronavirus had just been discovered. when the wuhan municipal government decided on january to "close the city" to control the outflow of population, more than million people had already left wuhan on the spring festival holiday, and it was too late to control the entire potentially infected population in the epidemic area. at present, china's high-speed railway and expressway transportation network has experienced great development. this fast and convenient transportation has led to a floating population that can leave the source area to quickly reach every part of the country, which makes it very difficult to quarantine the floating population leaving the source area through transportation stations. in addition, there is an incubation period after human infection, further increasing the difficulty of quarantine at traffic stations, which is also an important reason for the implementation of "city closure" control policies in many cities across the country. after -ncov was confirmed as being capable of transmitting from human to human, the chinese government implemented top to bottom national mobilisation. it fully investigated and isolated the population of wuhan, and also publicised the severity of the epidemic, and also increased awareness of the prevention of infectious diseases and raised people's vigilance through messages on television, mobile communications and the internet. in addition, according to the latest epidemic surveillance, the incubation period of the coronavirus is to days, with an upper limit of days. for this reason, the central government has issued an executive order to extend the spring festival holiday from january to february . many provinces are even requiring firms to not restart work until february, except those necessary for social operations related to the national economy and people's livelihood. extending the holiday is needed to avoid the returning people leaving home early and returning to work, so as to minimise the risk of the epidemic spreading again due to population fluctuations. there are limitations to this study. first, our analysis did not include other large-scale populations. for example, some are college students, because wuhan is the city with the largest number (> million) of college students in china and the world. the other parts include short-term business travellers, transit passengers and tourists. official media reported that the size of the populations during the spring festival holiday would reach more than million. this can be confirmed from the daily-confirmed cases of -ncov infection. although there is a small permanent population in wuhan whose household register belongs to provinces and cities such as beijing, shanghai, tianjin, hainan, and guangdong (in fact, shenzhen and guangzhou are two megacities), these provinces and cities still have large-scale temporary floating populations from and to wuhan because of the large population and well-developed economy. therefore, the number of confirmed cases of -ncov infection in these areas is far ahead of that in most other provinces that have a large floating population in wuhan. second, our sample has a certain deviation. the data on the origin of wuhan's floating population does not include hong kong, macao, or international migrants, which makes our research unable to estimate the population size of these regions. at present, some cases have been confirmed in surrounding asian countries, europe, north america and australia. third, limited to interdisciplinary research capabilities, our model does not include infectious disease analysis models such as sir to further analyse the potential and scale of -ncov spread, which may reduce the value of this research in the prevention and control of -ncov infections. finally, the results of the study are mainly applicable to the end of the spring festival holiday, and after the large-scale population comes back to work or study, the spread of the epidemic will be more complicated. we believe that the abovementioned limitations can be overcome. using big data such as location information of transportation and mobile internet, short-term floating populations can be included in the study to maximise the estimated population flotation and scale in wuhan. unfortunately, thus far we have not seen a rigorous study using big data to analyse the outflow of populations in the epicentre of an epidemic. this means that there is still a long way to go for the research and application of big data in the field of national and global public health. at the time of writing this paper ( january ), all provinces in china have reported confirmed or suspected cases of -ncov, every prefecture and city in hubei province has confirmed cases of -ncov, and transmission of -ncov has spread from imported to inter-regional. due to the fact that million migrants had left wuhan before the "closure of the city", our research reveals a high correlation between the number of wuhan's floating population and the number of confirmed cases. fortunately, the origin of wuhan's floating population is highly concentrated in hubei province and its surrounding provinces, of which the migrants with hubei household registers account for %, and more than % of the population is concentrated in the top districts and counties. this means that some areas will face a very high risk of epidemic outbreaks, but it is also conducive to centralised resources enabling prevention and control of the epidemic to avoid large-scale spread in other regions. more than million of wuhan's floating population have returned to their hometowns as potential carriers of the virus and may become carriers of the virus's re-transmission. due to china's urban and rural dualistic structure, most of these people are rural migrant workers with low levels of education. the results find that % of the migrants have rural household registers. these people, who frequently work outdoors or work overtime are more likely to be susceptible because of their poor diet and nutrition. at the same time, most of these people travel with - family members, and the susceptible and high-risk population over years old accounts for a large proportion of this floating population, which provides ideal conditions for the transmission of -ncov within families. to make matters worse, the rural areas where these people return to have very limited medical and public health services, and gatherings during the spring festival aggravate the risk of virus transmission in the community. so far, confirmed cases of -ncov continue to increase every day across china. the results of our model analysis indicate that, on the one hand, the correlation between the size of the floating population and the number of confirmed cases in wuhan has continued to increase over time, and by january, the correlation coefficient of these factors in hubei province had reached . , which means that the size of the floating population in wuhan is an important parameter for predicting the epidemic. on the other hand, we also found that the effect of the size of the floating population in wuhan is heterogeneous across regions. some areas have a large floating population in wuhan, including henan, anhui, and jiangxi provinces, and xiaogan city, jingzhou city, and the three county-level cities directly under the provincial government, and yet the number of confirmed cases of -ncov is apparently relatively small. however, we believe that the epidemic situation in these areas may be underestimated. considering the serious consequences of delays in diagnosis and loopholes in infection control in suspected or confirmed cases of sars in the sars epidemic in , it is necessary to strengthen surveillance in these areas to determine the causes of the fewer confirmed cases of -ncov in these areas. author contributions: l.l. conceived and proposed research ideas, c.f. and c.y. collected the data, c.f. undertook the main research work such as research methods, data analysis, and manuscript writing. c.f., l.l., w.g., a.y., c.y., m.j., m.r., p.x., h.l. and y.w. participated in draft review, contributed to data interpretation, and approved final manuscript. all authors have read and agreed to the published version of the manuscript. data sharing and outbreaks: best practice exemplified china coronavirus: what do we know so far? bmj nowcasting and forecasting the potential domestic and international spread of the -ncov outbreak originating in wuhan, china: a modelling study wuhan municipal health commission. the current epidemic of pneumonia in our city by wuhan municipal health commission geneva: world health organization national real-time epidemic website geneva: world health organization novel coronavirus -ncov: early estimation of epidemiological parameters and epidemic predictions report : transmissibility of -ncov epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study a novel coronavirus from patients with pneumonia in china a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster a novel coronavirus outbreak of global health concern emerging understandings of -ncov coronavirus infections-more than just the common cold from sars-cov to wuhan -ncov outbreak: similarity of early epidemic and prediction of future trends a novel coronavirus emerging in china-key questions for impact assessment another decade, another coronavirus report : estimating the potential total number of novel coronavirus cases in wuhan city report : estimating the potential total number of novel coronavirus cases in wuhan city modelling the epidemic trend of the novel coronavirus outbreak in china clinical features of patients infected with novel coronavirus in epidemic situation of the novel coronavirus in guangdong province published on xinhua news agency. chinese medical workers confirmed infected with coronavirus the chinese new year travel rush-the world's largest annual human migration wuhan municipal people's government. wuhan implements restriction to curb the spread of the epidemic real-time update on coronavirus outbreak internal migration and health in china the new york times. china grapples with mystery pneumonia-like illness health status and access to health care of migrant workers in china. public health rep acknowledgments: thanks to the national health committee for the migrant population data; the youth project of national social science foundation and the youth teacher project of central china normal university for support on previous construction of floating population database; binbin tang and junyue qian for their selfless help in the process of thesis writing. the authors declare no conflict of interest. key: cord- - gp mjen authors: garwood, tyler j.; lehman, chadwick p.; walsh, daniel p.; cassirer, e. frances; besser, thomas e.; jenks, jonathan a. title: removal of chronic mycoplasma ovipneumoniae carrier ewes eliminates pneumonia in a bighorn sheep population date: - - journal: ecol evol doi: . /ece . sha: doc_id: cord_uid: gp mjen . chronic pathogen carriage is one mechanism that allows diseases to persist in populations. we hypothesized that persistent or recurrent pneumonia in bighorn sheep (ovis canadensis) populations may be caused by chronic carriers of mycoplasma ovipneumoniae (mo). our experimental approach allowed us to address a conservation need while investigating the role of chronic carriage in disease persistence. . we tested our hypothesis in two bighorn sheep populations in south dakota, usa. we identified and removed mo chronic carriers from the custer state park (treatment) population. simultaneously, we identified carriers but did not remove them from the rapid city population (control). we predicted removal would result in decreased pneumonia, mortality, and mo prevalence. both population ranges had similar habitat and predator communities but were sufficiently isolated to preclude intermixing. . we classified chronic carriers as adults that consistently tested positive for mo carriage over a ‐month sampling period (n = in the treatment population; n = in control population). . we failed to detect mo or pneumonia in the treatment population after chronic carrier removal, while both remained in the control. mortality hazard for lambs was reduced by % in the treatment population relative to the control (ci = %, %). there was also a % reduction in adult mortality hazard attributable to the treatment, although this was not statistically significant (ci = % reduction, % increase). . synthesis and applications: these results support the hypothesis that mo is a primary causative agent of persistent or recurrent respiratory disease in bighorn sheep populations and can be maintained by a few chronic carriers. our findings provide direction for future research and management actions aimed at controlling pneumonia in wild sheep and may apply to other diseases. heterogeneity in infectiousness of individual hosts may dramatically affect pathogen transmission, as illustrated by the role of human superspreaders in the emergence of the severe acute respiratory syndrome-associated coronavirus (sars-cov), a zoonotic virus responsible for an acute human epidemic during (lloyd-smith, schreiber, kopp, & getz, woolhouse et al., ) . less is known about the importance of individual variation in infectiousness among diseases associated with chronically carried bacterial pathogens. chronic carriage/shedding is common features of several pathogenic bacteria, so understanding infection risks posed by chronic carrier individuals is relevant to management of infectious diseases across human, domestic animal, and wildlife health sectors (buhnerkempe et al., ; coyne et al., ; wertheim et al., ) . bighorn sheep (ovis canadensis) populations declined precipitously following the mid- s (buechner, ) , and bacterial pneumonia is a primary impediment to recovery (cassirer et al., ) . bighorn pneumonia frequently manifests as an initial allage outbreak causing %- % mortality (cassirer et al., ; enk, picton, & williams, ; spraker, hibler, schoonveld, & adney, ) , followed by annual epizootics among juveniles and sporadic pneumonia mortality among adults smith, jenks, grovenburg, & klaver, ) . pasteurellaceae (bibersteinia trehalosi, mannheimia haemolytica, leukotoxigenic pasteurella) and parasites (protostongylus sp.) (dassanayake et al., ; foreyt, snipes, & kasten, ; miller et al., ) . while mycoplasma ovipneumoniae (mo) is more strongly associated with pneumonia than previously targeted pathogens (besser et al., , no vaccines or efficacious antimicrobial treatments for mo currently exist. interventions for any pathogen(s) are also constrained by inaccessible terrain, as well as the complex movement patterns of bighorn sheep (cassirer et al., ; george, martin, lukacs, & miller, ) . we conducted our study in the south dakota black hills from august to may . this study site includes elevations of - , m (brown & sieg, ) , average annual precipitation (rapid city) of . cm rainfall and . cm snow, and temperatures of − to °c, with an average high of °c and an average low of the control population inhabited public and private land in pennington county and contained three subherds that rarely interacted (rapid creek, spring creek, and hill city, figure ; ° ′ ″ n, ° ' " w). this population utilized canyons for summer range and residential lawns during winter (smith, grovenburg, monteith, & jenks, ) . an all-age die-off occurred in , and pneumonia remained a major mortality source . the we captured bighorn sheep via chemical immobilization (bam; . mg/kg butorphanol, . mg/kg, azaperone, . mg/kg medetomidine, wildlife pharmaceuticals) delivered through dart injection or by aerial net-gunning (quicksilver air, inc. and hells canyon helicopters). we fitted sheep with very high-frequency (vhf) collars (m ob; advanced telemetry systems) with mortality sensors, which were activated if the collar was motionless for ≥ hr. after confirming pregnancy with ultrasonography (e.i. medical imaging), we fitted ewes with vhf vaginal implant transmitters (vits; m ; advanced telemetry systems; smith, walsh, et al., ) . during capture, we collected information on sex, age, mo carrier status and antibodies, and presence of other pathogens. we aged individuals up to . years old using tooth eruption (valdez & krausman, ) and classified adults > . years old as a single age group. we collected mo mucosal samples via three swabs, which were consecutively inserted deep into each of the nares and rotated around the cavity wall during removal (drew et al., ) . we returned two swabs to their sheath and immersed one in tryptic soy broth with % glycerol (hardy diagnostics; butler et al., ) . to sample for other aerobic bacteria that could contribute to respiratory disease, we rotated swabs along each tonsillar crypt and stored them similarly to nasal swabs. we collected blood for serum, held all samples at °c, and shipped them on ice to the washington animal disease diagnostic lab (waddl) or dr. thomas besser's lab (washington state university). we used real-time polymerase chain reaction (rt-pcr) to detect mo on nasal swabs (ziegler et al., ) . samples were positive if fluorescence generation exceeded the threshold before the th rt-pcr cycle, indeterminate if between the th and th cycles, and negative if not exceeded through cycles. we determined serum mo antibody presence by competitive enzyme-linked immunosorbent assay (c-elisa; ziegler et al., ) . we documented other pathogens on swabs through aerobic culture and pcr (besser et al., ) . we determined mo strain type using genomic dna extracted from m. ovipneumoniae broth cultures or swabs using dneasy blood and tissue kits (qiagen inc.), following manufacturer's instructions, or pcr-positive dna extracts obtained directly from waddl. mycoplasma ovipneumoniae extracts were genotyped using a multi-locus sequence typing approach that targets four loci. the targeted loci are partial dna sequences from the s- s intergenic spacer region (igs), the small ribosomal subunit ( s), and housekeeping genes encoding rna polymerase b (rpob) and gyrase b (gyrb). protocols and primers for pcr amplification of these loci were described previously ). commercial service laboratories (amplicon express and eurofins genomics) conducted bidirectional sanger dna sequencing of amplified pcr products using the same primers used in pcr reactions. we began mo testing in the treatment population in august . we obtained ≥ tests from every adult alive in the population before or shortly after chronic carrier removal (table and table s ). we classified individuals as chronic carriers (consistently positive), intermittent carriers (negative and positive tests), or noncarriers (all negative tests). we immobilized and relocated all chronic carriers from the treatment population to south dakota state university (sdsu). postremoval, we tested most individuals in both populations annually (table s and s ). f i g u r e a conceptual depiction of our experiment, where chronic carriers of mycoplasma ovipneumoniae are identified in two populations, but only removed in one. bighorn sheep can be classified as chronic carriers, intermittent carriers, and noncarriers; only chronic carriers need to be removed under our operating hypothesis. if chronic carriers are removed, the population should rebound as lamb recruitment improves. without intervention, the population will continue to decline indefinitely due to low lamb recruitment we monitored vit radio signals daily using handheld directional radio telemetry (telonics, inc.) starting april and . we located the dam to verify lamb presence when a vit was expelled. budgetary constraints prevented vit implantation in some pregnant ewes in the control population, so we visually monitored females without vits along with ewes that expelled their vits prematurely. if we observed a lamb, we attempted to hand capture it. we immobilized lambs we failed to capture as neonates at - months old. we weighed captured lambs, determined sex, and fitted them with expandable vhf collars (m ; advanced telemetry systems). we wore latex gloves and minimized handling of neonates to avoid abandonment (smith, walsh, et al., ) . the sdsu institutional animal care and use committee approved capture and handling procedures (approval number - a). we monitored adult collars for mortality signals times/week from march to may and lamb collars daily from capture until november; thereafter, we monitored lambs similarly to adults. when a collar indicated mortality, we located the carcass and examined the site for predator presence (scat, tracks, scrapes) and the cadaver for caching, hemorrhaging, and skeletal disarticulation (stonehouse, anderson, peterson, & collins, ) . we performed necropsies on adults in the field and shipped swabs to waddl for pathogen testing. when possible, we shipped lamb cadavers to waddl for necropsy. cause of death was sometimes uncertain; therefore, we used the knowledge gained from necropsies, evidence at the site, and behavioral observations to assign the likelihood of each individual's cause of death. cause-specific mortality categories for lambs and adults were "predation," "pneumonia," and "other," and, in addition for adults only, "human-caused." we created a probability for each category, and the resulting vector of prior predictive probabilities summed to one for each individual. if cause of death was certain, the vector contained a single, nonzero entry for the appropriate causeof-death category (walsh, norton, storm, van deelen, & heisey, ) . as an example of this process, a carcass might be scavenged shortly after dying, and movement of the collar could delay detection of the mortality by a week. the lack of disarticulation might rule f i g u r e ranges of study populations of bighorn sheep in the black hills, south dakota, usa, - out predation, but the carcass's desiccated state would make it difficult to tell whether pneumonia or another internal malady caused death. if we had previous behavioral evidence that indicated pneumonia, in this example we would assign a % predictive probability to "pneumonia," % to "other," and % to all other categories. we modeled weekly survival rates, incorporating covariates for treatment, strain type exposure , testing pcr positive for mo, biological year (gaillard, festa-bianchet, yoccoz, loison, & toigo, ) , sex (jorgenson, festa-bianchet, gaillard, & wishart, ) , and age (loison, festa-bianchet, gaillard, jorgenson, & jullien, ) as factors affecting survival. we coded the treatment, sex, and an individual's positive test effects as binary variables (treatment population = , control population = ; males = , females = ; ≥ positive = , no positives = ). we treated an individual's age as a time-varying, categorical variable separated into groups ( = - years old, = - years old, = + years old). our adult global model calculated log unit cumulative hazard as the baseline log unit cumulative hazard rate. for the i th individual during the j th week, we denoted β treatment as the treatment effect, β positive test as the positive test effect, β strain as the strain type effect, β year as the year effect, β age as the individual's age effect, and β sex as an individual's sex effect. we signified the week effect with ρ j . we modeled daily survival rates, incorporating treatment (i.e., population identity), year (gaillard et al., ) , strain type exposure (cassirer ta b l e summary of bighorn sheep pathogen testing results and survival estimates in the treatment and control populations, we coded treatment and individual sex effects as with adults. we designated year as a binary variable ( = , = ) and birth timing consisted of three groups: lambs born within ± days of the median date of lamb births in a given year, those born > days before the peak period, and those born > days after the peak period . we coded strain type exposure as categorical (exposure to introduced strain = , exposure to resident strain = , exposure to neither = ). based on strain typing data, lambs in the spring creek subherd were exposed to the introduced strain in , and the resident strain in . all lambs in rapid creek and hill city subherds were classified as only exposed to the resident strain for the duration of the study. since we removed all carriers of mo in the treatment population in january and there were no mo-positive tests postremoval, we classified treatment lambs as being exposed to neither strain for the entire study. birth weight was measured to the nearest . kg. for late-caught lambs, we imputed missing birth weight and birth timing values using the empirical distributions of these variables for lambs caught as neonates (gelman et al., ) . our global model calculated daily log unit cumulative hazard as ln(Λ i,j ) = γ + β treatment × treatment i + β strain [strain type i ] + β year × year i + β sex × sex i + β birth timing [birth timing i ] + β birth weight × birth weight i + ρ j . the γ, β treatment , and β sex parameters were included in the model in the same way as in the adult model. for the i th individual during the j th day, we denoted the year effect as β year , β strain as the strain type exposure effect, β birth timing as the birth timing effect, and β birth weight as the birth weight effect. we signified the day effect with ρ j . we then calculated cause-specific mortality while incorporating observer uncertainty into parameter estimation (walsh et al., ) . specifically, we treated the true cause of death for each individual as a latent, unknown variable with an assigned vector of prior predictive probabilities. as described above, these priors specified the observer's belief that each cause of death was the true cause of death given their assessment of the available evidence (table s ) . we imputed the true cause of death, using a data augmentation approach that generated a cause of death at each markov chain monte carlo (mcmc) iteration (gelman et al., ) , based on a categorical distribution with a parameter vector equal to the prior predictive probability vector specified for that individual. using random starting values, we ran three mcmc chains for , iterations and removed the first , repetitions for burn-in. we looked for evidence of nonconvergence of the chains via graphical checks, and none was observed for any of the following analyses. we calculated watanabe-akaike information criteria (waic) from each model to identify models that best described the evidence in the data (gelman et al., ) . we considered models differing by ≤ waic as alternatives to the top ranked model but preferred the simplest model (burnham & anderson, ) . we based our conclusions on parameter estimates from the best model. we radio-collared adult bighorn sheep between august and may : in the treatment ( rams, ewes) and ( rams, ewes) in the control population. this constituted % and ~ % of adults in the respective populations by the study's end. categorized by age at the end of the study, we collared ( treatment, control) - year olds, ( treatment, control) - year olds, ( treatment, control) - year olds, and ( treatment, control) ≥ year olds. we tested all treatment population adults that survived long enough to be tested ( rams, ewes) for mo over sampling events (table ) . fifty-one ( %) swabs tested negative with rt-pcr, ( %) tested indeterminate, and ( %) tested positive. two females were classified as chronic carriers of the bh- strain (n = positive tests). the other adult that tested positive subsequently tested negative and died before experimental manipulation. we classified all other individuals tested twice as noncarriers (n = individuals). we removed the two chronic carriers on march . after removal of chronic carriers, we did not detect mo in samples ( negative and indeterminate) collected from individuals ( males, females) in the treatment population (table and table s ). we collected serum from individuals, and antibodies were detected in ( %); ( %) tested indeterminate, and between january and may , we collected samples from control population bighorn sheep (table and table s ). we obtained mo-positive samples ( %), indeterminate samples ( %) and negative samples ( %). we were able to strain type of the positive samples. we found that samples were the resident bhs- strain also detected in the treatment population, but samples were typed as bhs- (introduced and ( %) tested negative. we lacked serum from individuals. we we monitored survival of radio-collared adults march - may . we documented mortalities ( males, females, % of adults) in the treatment population and ( males, females, % of adults) in the control population (figure a ). our best survival model was ln(Λ ij ) = γ + β treatment × treatment i + ρ j , which we used to calculate log weekly cumulative mortality hazard estimates (w = . , table s ). the model indicated chronic carrier removal reduced adult hazard by %, but was not statistically significant with the % credible interval (ci) including zero (ci = % reduction, % increase; table , figure s ). an analysis that excluded the spring creek subherd, which was exposed to multiple mo strains, produced similar estimates (hazard reduction = %, ci = % reduction, % increase). this corresponds to a % annual survival rate (ci = %, %) in the treatment population and % (ci = %, %) in the control population (table ) . hazard of pneumonia-induced mortality for adults in the treatment population was significantly lower than in the control population (probability difference = − %, ci = − %, − %; figure c ). no pneumonia was detected in the treatment population, and the probability of pneumonia-induced adult mortality was lower ( %, ci = %, %) than in the control herd ( %, ci = %, %). conversely, predation was more likely to be assigned as cause of death in the treatment population ( %, ci = %, %) than in the control ( %, ci = %, %; probability difference = %, ci = %, %). we our best lamb survival model was ln(Λ ij ) = γ + β treatment × treat- table s ). lamb birth weight (mean = . kg, se = . , n = ), sex, and birth timing were not supported as predictors of survival. we calculated log daily cumulative hazard measurements based on this model ( figure s ) and determined that chronic carrier removal had a negative effect on daily lamb hazard ( % reduction in the treatment population, ci = %, %; table ). this corresponds with a % annual survival rate (ci = %, %) in the treatment population and % (ci = %, %) in the control (table ) . we observed higher lamb mortality in than in (β year = . , ci = . , . ). pneumonia-caused mortality was significantly less likely in the treatment population (probability = %, ci = %, %) than in the control population (probability = %, ci = %, %), with a probability difference of − % (ci = − %, − %) (figure d ). lambs that died had a % probability of dying from predation in the treatment population (ci = %, %), which was significantly higher than the control population ( %, ci = %, %; probability difference = %, ci = %, %). we found that pneumonia can be maintained in bighorn sheep populations by a few individuals chronically carrying mo. after removing these individuals, we detected no deaths attributable to pneumonia and % of lambs survived to months of age, similar to other healthy populations in our study region ( . %- %; parr et al., ; zimmerman, ) . in contrast, we detected pneumonia-induced mortality in adults and juveniles in a control population where mo carriers remained. average lamb survival to months in the control population was %, which is similar to other unhealthy populations ( %- % of collared lambs surviving; cassirer et al., ; grigg et al., ; . we detected other pneumonia-associated pathogens in both populations, but their presence failed to induce pneumonia in adults or lambs in the absence of mo (table ) . this finding makes physiological sense: while other pathogens contribute to disease , mo appears necessary, by disrupting mucociliary clearance, for bighorn sheep to establish lung infections (cassirer et al., ; niang et al., ) . although leukotoxigenic pasteurella was detected in the treatment population before removal and not afterward, the three individuals harboring it were not removed (table s and table s ). our results indicate that mo is warranted as a focal pathogen in efforts to eliminate pneumonia in wild sheep populations. we found intermittent carriers in our control population but none in our treatment population (table ) . strain typing of samples from intermittent carriers in the control population revealed that eight changed from noncarriers to carriers when infected with a strain previously found in bighorn sheep in deadwood, south dakota and western nebraska (kamath et al., ) . these individuals therefore were not intermittently carrying a single strain of mo. more likely, they lacked strain-specific immunity and were acutely carrying the introduced strain of mo . importantly, they were not contributing to the persistence of the original strain. the role of intermittent carriers in population-level dynamics of mo is not known ; however, our assumption is that chronic carriers are necessary for persistence. our study indicates that in some cases intermittent carriage can be attributed to the introduction of a new strain type. future studies could consider invasion of new strains as a potential factor influencing mo carriage patterns. although our study demonstrates improved lamb survival resulting from removing chronic carriers, the impact on adult survival is not as pronounced. we detected a statistically significant reduction in pneumonia-induced adult mortality in the treatment population relative to the control, but other sources of mortality in the treatment population offset this effect. for adults, our best survival model included a treatment effect and was significantly better (i.e., ≥ Δwaic) than models lacking this effect; however, the effect was not statistically significant. this finding may indicate that the treatment effect was biologically important, but a larger sample size is needed to assess statistical significance given the overall high survival rates of both the treatment and control populations. previous studies found that adult survival generally rebounded to or above previous levels in the years following all-age die-offs (manlove, cassirer, cross, plowright, & hudson, ; plowright et al., ) . clarifying it remains unclear which host factors contribute to chronic carriage and how to minimize the number of tests necessary to identify chronic carriers. plowright et al. ( ) found that age and homozygosity at a specific locus were associated with persistent carriage of mo in bighorn sheep, suggesting possible host factors that might contribute to variation in infectious period and carriage rates among populations. coinfections, underlying disease, and high exposure frequency and/or dose may also shape host resistance to infection and increase likelihood of chronic or intermittent carriage (fox et al., ) . chronic carriers might also be individuals that adopt a strategy of tolerance (limiting the harm caused by a given parasite burden) rather than resistance (limiting parasite burden) to combat mo. this predisposition for tolerance has a genetic basis and is variable among individuals within a species (råberg, graham, & reed, ) . identifying factors associated with carriage status would provide insight into temporal variation in disease dynamics and population response to infection. the ability to determine the likelihood of intermittent versus chronic carriage at an individual or population level would also help minimize the sampling effort required to efficiently identify chronic carriers. our results indicate the minimum required sampling intensity will vary across populations. given the cost of identifying chronic carriers, wildlife managers might question whether complete depopulation followed by repopulation is preferable to selective removal. however, complete depopulation of wildlife is not always feasible, especially in rugged or remote terrain (courchamp, chapuis, & pascal, ) . furthermore, while depopulation removes the pathogen along with its host, ensuing reintroductions may fail (griffith, scott, carpenter, & reed, ) depends on how the disease is spread and maintained within and between populations. as infectious disease outbreaks increase globally (jones et al., ) , broadening our understanding of various transmission patterns will be integral to mitigating disease outbreaks and conserving at-risk wildlife populations. wieseler, j. jenson., and b. felts were integral to completing field work. any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the u.s. government. none declared. tyler j. garwood https://orcid.org/ - - - x daniel p. walsh https://orcid.org/ - - - association of mycoplasma ovipneumoniae infection with population-limiting respiratory disease in free-ranging rocky mountain bighorn sheep (ovis canadensis canadensis) bighorn sheep pneumonia: sorting out the cause of a polymicrobial disease historical variability in fire at the ponderosa pine -northern great plains prairie ecotone, southeastern black hills bighorn sheep in the united states detecting signals of chronic shedding to explain pathogen persistence: leptospira interrogans in california sea lions model selection and multimodel inference: a practical information-theoretic approach ( nd assessing respiratory pathogen communities in bighorn sheep populations: sampling realities, 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techniques for capturing bighorn sheep lambs south dakota bighorn sheep management plan pathologic changes and microorganisms found in bighorn sheep during a stress-related die-off approaches to field investigations of cause-specific mortality in mule deer mountain sheep of north america using expert knowledge to incorporate uncertainty in cause-of-death assignments for modeling of cause-specific mortality the role of nasal carriage in staphylococcus aureus infections. the lancet infectious diseases heterogeneities in the transmission of infectious agents: implications for the design of control programs safety and immunogenicity of a mycoplasma ovipneumoniae bacterin for domestic sheep evaluation of an augmentation of rocky mountain bighorn sheep at badlands national park, south dakota. phd dissertation key: cord- -ny qr a authors: belo, vinícius silva; struchiner, claudio josé; werneck, guilherme loureiro; teixeira neto, rafael gonçalves; tonelli, gabriel barbosa; de carvalho júnior, clóvis gomes; ribeiro, renata aparecida nascimento; da silva, eduardo sérgio title: abundance, survival, recruitment and effectiveness of sterilization of free-roaming dogs: a capture and recapture study in brazil date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: ny qr a the existence of free-roaming dogs raises important issues in animal welfare and in public health. a proper understanding of these animals’ ecology is useful as a necessary input to plan strategies to control these populations. the present study addresses the population dynamics and the effectiveness of the sterilization of unrestricted dogs using capture and recapture procedures suitable for open animal populations. every two months, over a period of months, we captured, tagged, released and recaptured dogs in two regions in a city in the southeast region of brazil. in one of these regions the animals were also sterilized. both regions had similar social, environmental and demographic features. we estimated the presence of females and males during the period of study. the average dog:man ratio was dog for each and human beings, in the areas without and with sterilization, respectively. the animal population size increased in both regions, due mainly to the abandonment of domestic dogs. mortality rate decreased throughout the study period. survival probabilities did not differ between genders, but males entered the population in higher numbers. there were no differences in abundance, survival and recruitment between the regions, indicating that sterilization did not affect the population dynamics. our findings indicate that the observed animal dynamics were influenced by density-independent factors, and that sterilization might not be a viable and effective strategy in regions where availability of resources is low and animal abandonment rates are high. furthermore, the high demographic turnover rates observed render the canine free-roaming population younger, thus more susceptible to diseases, especially to rabies and leishmaniasis. we conclude by stressing the importance of implementing educational programs to promote responsible animal ownership and effective strategies against abandonment practices. a a a a a the relationship between dogs (canis familiaris) and men goes back to the beginning of civilization, about , years ago [ , ] . it is generally accepted that dogs were domesticated from the wolf (canis lupus pallipes or c. lupus variabilis) in a process of symbiosis that evolved through selective breeding [ ] . indeed, dogs are termed as 'domestic' or 'domesticated' animals due to its association with humans and to the role that humans exercised in the emergence of this lineage [ ] . since domestication, this relationship became even more intense and dogs are ubiquitous in the cultural context of every society, constituting the most abundant carnivore animal on the planet [ ] . dogs have been associated with their owners' welfare and well-being [ , ] and have started to play different functions [ ] due to their malleable personalities, docile behavior and utility as guardians and hunters [ ] . dogs that are not under immediate human supervision and have unrestricted access to public property are named "free-roaming" or free-ranging [ ] . these terms encompass both owned dogs (family and some neighborhood dogs) and ownerless dogs (stray or feral) [ ] . the existence of these dogs that can circulate freely in the streets can be harmful to both the animals and to human beings [ ] . the abandonment and breeding of dogs in unrestricted environments have been attributed to behavioral, religious, cultural, ecological and socioeconomic factors, constituting important issues in public health and animal welfare [ , ] . unrestricted dogs, in general, have their psychological and physical health compromised, are more likely to acquire infectious diseases and have a lower life expectancy compared to pet dogs [ ] [ ] [ ] . their presence can be detrimental to humans since they are associated with the occurrence of biting incidents, transmission of diseases, damage to wild animal populations, accidents and pollution [ ] [ ] [ ] [ ] [ ] [ ] . different strategies are used to control the population of unrestricted dogs [ ] . elimination by killing is not considered effective, since the number of removed animals is compensated for the increased entry and survival of the remaining ones. in addition, this method is the subject of much criticism based on ethical issues [ ] [ ] [ ] . as a result, actions towards promoting responsible animal ownership, the strengthening of legislation against abandonment, and surgical control have been established in different countries [ , ] . annually, thousands of unrestricted dogs are sterilized in veterinary clinics and in campaigns run by governments and non-governmental organizations. nevertheless, the effectiveness of this measure, in the long term, has been poorly evaluated [ , ] a proper evaluation of actions that aim at controlling the free-roaming canine population requires non-biased estimates of parameters driving the dynamics of the target population [ , ] . even though several studies have yielded estimates of the population size of free-ranging dogs, most of them used inadequate analytical methods and were susceptible to biases, which casts doubt on the validity of these estimates, as evidenced in a recent systematic review [ ] . additionally, there is no published data of capture and recapture procedures that consider the canine populations as open, that is, subjected to deaths, births and migrations [ ] . despite the perceived need and usefulness of such parameter estimates and recommendations for the most appropriate approaches applicable under such study designs [ ] , survival and recruitment estimates of free-ranging dogs had not been obtained using methods of capture and recapture. in this study, we present estimates of abundance, survival and recruitment rates, and the probabilities of capture of two free-roaming dog populations by means of analytical models for open populations, so far unexplored in previous studies. these dogs were followed for months in a city located in the southeast region of brazil. we report temporal variations of the estimates during the study period regarding gender and the effectiveness of surgical sterilization. been approved by cepea-commission of ethics in research involving animals of the federal university of são joão del rey (protocol no. / ). prior to the implementation of the activities described in the next section, we performed a pilot study to define the areas of study and to identify potential problems requiring further attention. the pilot study lasted for four days, each day spent in a different neighborhood of the city. each one of the four neighborhoods belonged to four different eligible areas defined with municipal health authorities based on previous information on the occurrence of freeroaming dogs and on the feasibility of carrying out the research. those with similar features and with the highest raw number of captured and released animals were selected. data acquired in this stage were not used in the analyses. we conducted seven capture and recapture procedures in a period of one year and two months, one every two months. dogs found wandering in the streets during the capture period were included in the study, provided an owner with a dog leash did not accompany them. adapted vehicles drove around all the streets of the study areas screening for free-roaming animals. the work team consisted of one driver, two municipal health agents, one veterinarian and two individuals responsible for collecting and recording data. in area a, activities took place in the first week of the collecting months, while in area b, they took place in the second week of the same month. screenings always followed the same route, so that they covered all the streets of each region at least once. the same team collected the data in both areas. captured dogs of areas a and b were taken to the health surveillance reference center of the city (crevisa) in adapted vehicles of public health service. in crevisa they underwent clinical tests conducted by veterinarians and were screened for canine leishmaniasis (canl). the diagnosis of canl was made in the parasitology laboratory of universidade federal de são joão del rei through the techniques of "enzyme-linked immunosorbent assay" and "indirect fluorescent antibody test". seropositive dogs were euthanized according to the recommendations of the brazilian ministry of health [ ] . dogs that tested negative were microchipped for identification if recaptured. these animals were also de-wormed and received a vaccine against rabies and another against distemper, leptospirosis, hepatitis, parainfluenza, parvovirus, coronavirus and adenovirus. dogs captured in the area b (intervention) were sterilized (s appendix). healthy animals were returned to the same place where they had been captured, after screening for canl and total rehabilitation of the surgical procedure (area b dogs) (s appendix). recaptured animals were re-examined. animals screened and found negative for canl were released again. animals that tested positive were euthanized. all dogs, even those not captured, were photographed for posterior identification in the same sample interval and in recaptures. for identification, distinctive characteristics of the dogs were sought in their craniolateral and/or dorso-caudal portions. for analytical purposes, dogs not physically captured but photographed were considered captured. this information was added to the database serving as input for the estimation of the population dynamic parameters. we released informative materials to the local population with the purpose of increasing their awareness regarding responsible animal ownership and visceral leishmaniasis (s appendix). we entered the individual history of capture and recapture of each animal into a microsoft excel ( ) database formatted as "encounter history" for captured animals tagged alive [ ] . euthanized animals carried a negative sign, indicating the occurrence of death during the capture procedure. there were no deaths attributed to other factors. general procedure. the jolly-seber model with popan parametrization served as the starting structure for model fitting [ ] . we estimated the following three parameters using his approach: φ i (survival): probability of a marked or unmarked animal surviving (and not migrating) between the captures i and i+ . p i : (capture probability): the probability of finding or seeing a marked or unmarked animal in a given capture i, given the animal is alive and in the area of capture. b i : (probability of entrance): considering the existence of a "super-population", comprised of all animals that would ever be born to the population, this parameter constitutes the probability of an animal of this hypothetical "super-population" entering the population between the occasions i and i+ . the parameters above allow for the estimation of recruitment (b: number of animals that enter the population between two capture procedures) and population size (n). we used mark, version . for fitting the statistical models. goodness of fit of highly parameterized models. we evaluated the goodness of fit (gof) of the model with the largest number of parameters prior to fitting models that were more parsimonious [ ] . this step was necessary to check the premises of the jolly-seber approach. we checked model's gof based on tests and of the release suite of mark software, the gof statistics obtained via the bootstrap, as well as the "median c-hat" statistics. among the procedures, we adopted the one that indicated the highest variance inflation factor (c-hat). we first considered the model with the variables "sex" (male or female), "area" (a or b), "time" (sampling period), and their respective interaction terms. a c-hat value of . suggested sparsity in different periods of capture. we changed our model search strategy accordingly and partitioned the previous model into two models: a model with "sex", "time" and interactions and a second model with "area", "time" and interactions. c-hat estimated in these cases was . and . , respectively for each model, and there were few indications of sparse data. modeling procedures. the gof analysis reported above prompted us to investigate factors associated with survival estimates, probability of capture and probability of entry separately for the variables "sex" and "area". in both cases, we built models considering timedependent or time-independent parameters and the presence of interactions between the variables "sex" and "time" or "area" and "time". we also fitted additive models containing parameters expressed as a function of two or more factors, in this case, area and time or sex and time, without the presence of interactions. in total, we fitted models in both groups (s appendix). all models supported temporal variations for the "probability of entry" (b i ). model selection followed the usual approach by searching for the most parsimonious structure that retained the best balance between explained variability and precision of estimates. we ranked all models based on akaike's information criterion corrected for finite sample sizes (aicc). this statistic provides a summary balance between the goodness of fit to the data of each model and the number of necessary parameters. "data cloning" was used to identify the correct number of estimated parameters [ ] . the presence of overdispersion in the data indicated the need to further correct the aicc statistics by the c-hat values to obtain the quasi-aicc statistics (qaicc). lower values of these latter statistics point to models that were more parsimonious [ ] . after ranking all models based on qaicc, we evaluated the force of evidence in favor of each model (aic weight-"w"). this statistic can be interpreted as the conditional probability of a given model being the best among the set analyzed. thus, higher values of "w" indicate higher force of evidence in favor of the model. models with values of "w" lower than . were disregarded. we further evaluated the importance of each variable in a context of a set of models by adding up the weight (w) of each model containing a given variable [ ] . we repeated this procedure for all predictors considered. variables with higher weights are considered more important than those with lower weights in explaining the variance observed in the data. parameter estimation. estimates for the parameters survival probability, probability of capture, probability of entry in the population, abundance and recruitment rate relied on the technique known as "model averaging" [ ] . under this approach, we calculated the weighted average of parameter estimates from all models fitted to data using as weights the relative support (w) of the respective model. therefore, this technique accounts for both sources of variance: the specific conditional variation present in each one of the models and the nonconditional variation present in the model selection process. in this way, parameter estimates express more faithfully the sources of uncertainty associated with the estimation process. in time-dependent models under popan not all parameters are identifiable [ ] . this is the case of the probability of capture in the first and in the last captures (p and p k ), the probability of entry between the first and the second captures (b ) and between the penultimate and the last captures (b k- ), and the survival probability between the penultimate and the last captures (φ k- ). thus, only the remaining parameters whose estimation was possible are described here. the effectiveness of sterilization was analyzed by comparing the evolution of abundance and of the other parameters estimated in the areas: a (control) and b (intervention). we estimated dog:human ratio by the ratio of population size and the dog mean abundance in each of the areas. during the study period, dogs were identified individually in region a (control) and in region b (intervention). the proportion of males in areas a and b was % ( dogs) and % ( dogs) respectively. one hundred and thirty-three animals ( males and females) were captured in more than one effort of captures. one hundred and thirty-eight dogs ( %) were sterilized. twenty-four were euthanized for testing positive to canl. sixty-six different individual histories of captures were registered and of them included animals not captured in the first effort. all recaptures and visualizations took place in the same area where the dogs were initially detected. most free-roaming dogs were neighborhood dogs, i.e. several human residents in the area provided the needed resources to them [ ] . models including the variable "gender". we fitted models containing the variable gender to the data (s appendix). five had w-statistics greater than % and are shown in table , along with statistics qaicc, Δqaicc (difference, in module, between qaicc values of the best model and the analyzed model). the relative support for each model is also expressed as the ratio of its w-statistics to the largest value of this statistic among the five models considered. the model in which survival, probability of capture and probability of entry varied with time, but not between male and female dogs, was considered the most parsimonious (w = . %). the weight for this model was . times higher than the model in which survival varied additively with gender; and . times higher in relation to the model in which the probability of capture varied between genders. other models had weights lower than % and low support, when compared to the most parsimonious model. the sum of each variable's weight (w) considering all models (table ) are presented in s appendix. time-dependent parameters displayed higher weights. survival and capture probabilities varied between genders but these variables' "w" conferred weak support to this statement. for entrance probability, there was no evidence for the existence of group variation. models with the variable "area". models containing the variable "area" behaved similarly to the previous set containing the variable "gender". table presents the six models in this group with w-statistics greater than %. results for the remaining models are described in s appendix. the model containing time-dependent parameters, but constant between areas control (a) and intervention (b), was the most parsimonious in this group. its weight, however, was lower when compared to the models containing the variable "gender" (table ). it had . times more support from the data than the model in which there was variation in survival between areas, and . more support than the model in which the probability of capture also varied between areas. differences were significantly higher when comparing the most parsimonious model to the remaining models since the latter models received even lower support from the data. we observed stronger weights associated with time-dependent variables (s appendix). however, the observed weights were lower than those associated to the variables in the set of models containing the variable "gender". we also observed stronger weights in variables describing differences in survival and probabilities of capture between areas. the remaining variables were associated with lower weights. in particular, the probabilities of entry did not vary between control and intervention areas. models with the variable "gender". we estimated a population abundance of females and males in the target population in the entire study period. table depicts gender-specific parameter estimates and their respective confidence intervals (ci). they result from model-specific estimates weighted by the relative support (w) of the respective model. taken together, these results show that gender-specific differences regarding the estimated parameters were not relevant. in contrast, time-dependent differences were significant. survival probabilities increased steadily, going from . in the interval between the first and second captures, to . between the fifth and sixth. on the other hand, probability of entry in the population was close to zero between the fifth and the sixth captures, and varied between . and . in other intervals. probability of capture reached the highest value in the second capture ( . ), and decreased subsequently until the fifth capture when it reached its lowest value ( . ). estimates of abundance highlight the majority of males in its composition. additionally, there was a higher entry of male dogs in all intervals in which the number could be estimated. population increased in size during the study. we estimated the presence of approximately females and population dynamics and effectiveness of sterilization of free-roaming dogs males in the second capture, and females and and males, respectively, in the fifth and sixth captures. models with the variable "area". we estimated the presence of dogs in area a (control) and in area b (intervention) throughout the study period. estimates of additional parameters stratified by control and intervention areas are presented in table . they reflect the weighting mechanism by the relative support of all models analyzed as explained in the methods section. analogously to the models containing gender, differences between the estimates of each area were small, even though they were slightly higher than those seen between genders. owing to the fact that stronger weights were attributed to models that did not show a difference between strata in either set of models, estimates of survival, capture probabilities and entry probabilities for the areas were similar to those described for gender. on the other hand, the recruitment was similar in both areas, contrasting with our findings comparing males and females. population size increased in both areas. abundances seen in the second capture were smaller, animals in area a and in area b, contrasting with abundances observed in the fifth capture, dogs in area a and in area b. dog:human ratio in area a was one dog to human beings. in area b, this ratio was one dog to humans. we estimated critical parameters (survival, recruitment and abundance) that describe the population dynamics of free-roaming dogs based on a capture and recapture study design and on models suitable for open populations. our study demonstrated the increase in population size in both areas, the predominance and greater recruitment of males, the temporal variability in recruitment and in survival probabilities, the lack of effect of sterilization on population dynamics, the influence of abandon and of density-independent factors and a high demographic turnover. such information on the dynamics of free-ranging dogs are useful for informing control interventions of unrestricted dog populations and against canine visceral leishmaniasis and rabies, both neglected tropical diseases endemic to various countries. the dog:man ratio observed in our study was smaller than that observed in counts performed in urban regions of nigeria ( dog to men) [ ] and that among rural dog populations in india ( dog to men) analyzed by mean of beck's method [ ] . it was larger, however, than the counts obtained by hossain et al. [ ] in a rural area of bangladesh. demographic, socioeconomic, environmental and cultural factors able to explain differences in abundances between and within regions have been underexplored in the literature [ ] . abundance of free-roaming dogs in general is lower in rural than urban areas [ , ] . regions under poorer socioeconomic conditions and higher population densities tend to have a larger concentration of dogs [ ] . in the present study, abundance possibly reflects the intermediary socioeconomic condition, the urban environment and low population density of the study areas as well as the different methodology applied. for most animal species, survival is the demographic parameter with highest impact on population size [ ] . few studies, however, aimed at estimating the survival of free-ranging dogs in urban environment. reece et al. [ ] used data from a sterilization program to estimate the survival of castrated females in jaipur, india. annual survival of females aged over one year old was . and of females in their first year of life was . . the assumptions leading to these estimates were implausible and might have biased the results. pal [ ] conducted four annual capture efforts, in bengal, india, and estimated the canine mortality from the number of dogs observed in the captures after the first one. annual survival for adult dogs was . , and for dogs in their first year of life, . . this study did not report capture probabilities and included in estimation only dogs found dead. this approach possibly contributed to an overestimation of the survival probability. survival probability reported by beck [ ] , in a study conducted in baltimore, canada, with dogs of all age groups, was . . this author relied only on existing information regarding the number of dead dogs, also possibly leading to an underestimation of mortality and consequently to an overestimation of survival probability. although limited, estimates obtained in the literature suggest that survival is lower in young free-roaming dogs [ , ] , a pattern already seen in different animal species [ , ] . once the proper identification of the dogs' ages was outside the scope of our project, estimates in the present study refer to the general survival probability of the population and not age-specific probabilities. annual survival in our study was higher than that estimated for dogs aged less than one year [ , ] , and lower than the survival probability estimated for adult dogs [ , ] and for beck's study population [ ] . the low survival probability identified in the population results from the different sources of mortality experienced by free-roaming dogs in the study setting. residents often reported roadkill and poisoning episodes during the study period. the high prevalence of canl-seropositive dogs, especially in the first months of the study, is another relevant factor leading to the removal of many animals by euthanasia. additionally, government actions towards street dogs were restricted to rabies vaccination. the lack of additional prophylactic measures or treatment may have contributed to the increased susceptibility of dogs to infections and other conditions. females have lower survival rates [ , ] in a large number of animal species due primarily to the effects of reproduction. given the predominance of males in different studies, it is hypothesized that this pattern also happens in the canine populations [ ] . we observed no difference in survival probabilities between genders, although a higher abundance and recruitment of males occurred. most pet owners prefer male dogs since they do not get pregnant and are better guard dogs [ , ] . therefore, the higher survival of male puppies of owned but free-ranging dogs or of pet dogs subsequently abandoned by their owners could probably explain the predominance of males in the free-roaming dog population. to our knowledge, we report for the first-time the temporal evolution of the survival probability of free-roaming dogs. annual point estimates of survival probability found in the literature do not bear a longitudinal structure. our results show that survival of unrestricted dogs displays variations, even in short temporal scales. among the models fitted to the data, those in which survival did not vary with time had significantly lower weights, indicating that a constant value is not appropriate to representing the entire period. estimates of survival probabilities in other mammal species also show a temporal dependence, especially in young individuals [ ] [ ] [ ] . long-term studies are required to uncover the intrinsic and extrinsic determinants driving these temporal dependencies. this would be useful for understanding the population dynamics of free-ranging dogs and improving the validity and precision of predictive modelling procedures. such studies are difficult to perform, and thus are rare in the literature [ ] . despite being a short-term study, survival, recruitment and population size displayed an increasing tendency. this pattern suggests that density-independent factors could be responsible for driving the variations observed in survival probabilities of dogs in both areas. density-dependent mechanisms are the subject of several studies focusing on different animal species [ ] [ ] [ ] [ ] . in epidemiological and ecological modeling, one assumes that survival and recruitment rates in free-ranging dogs are driven by the availability of resources in the environment, a density-dependent mechanism [ ] . however, as pointed out by de little et al. [ ] , extrinsic factors not regulated by density may determine fluctuations in population size when those populations have not yet reached their carrying capacity or when environmental conditions are favorable. according to morters [ ] , human beings are the major agents responsible for providing care and adequate food for dogs. as a result, human related factors such as living together with free-ranging dogs, the low dog-human ratio and the availability of residents' resources to maintain these animals, may explain why the increase in density had no influence upon mortality and recruitment. reducing the availability of shelters and food is an ethically questionable measure for population control of free-roaming dogs. however, this alternative has been presented in a recent study [ ] . it is not possible to affirm whether population growth, attributed to the large number of animals entering the population, would keep the reported increasing trend constant if the study had a longer duration. maximum survival and lack of recruitments between the fifth and the sixth captures suggest potential instabilities. in the presence of increasing abundance, density-dependent factors could start to play a stronger role in regulating the population [ , ] and in the behavior of residents regarding their support to dogs. there is considerable uncertainty in assessing the role played by vital rates and intrinsic and extrinsic factors in driving the population size of free-ranging dogs and other mammals [ , , , ] . estimates of recruitment obtained from capture and recapture models do not allow us to disentangle the sources of entry attributable to births and immigration. we observed no females with their brood along the study period. we might infer that breeding females were located in less visible areas or put to adoption by the city public service and returned to the streets after the lactation period, even though such registries were rare. in the study of morters et al. [ ] , as well as in the present study, recruitment was driven, predominantly, by the arrival of adult animals. the recruitment contingent may comprise dogs born in the region and not identified as puppies, dogs from other regions that migrated to the study region or were relocated by residents who raised them unrestrictedly, previously restricted dogs that changed status to being freely raised, or dogs abandoned nearby that later joined the population. the study areas are geographically isolated from their neighboring regions and are located next to a highway where dogs were frequently abandoned. therefore, the latter mechanism seems more plausible to account for the increase in population size rather than the spontaneous immigration of dogs. although there are heterogeneities [ ] , free-ranging dogs are territorial animals that, in general, do not move across long distances, unless forced by unfavorable environmental conditions [ ] . the low mobility of dogs in a favorable environment is supported by our data, since there were no animal movements between the areas a and b. the replacement of a great number of dogs that died or emigrated by dogs that are born or immigrate, as observed in our study populations, drives the population structure and gives rise to health problems that result from these structures. a population with a high turnover may be more susceptible to diseases [ ] . a high population turnover is the major obstacle for the success of control strategies against rabies in developing countries [ ] . vaccination strategies under such population dynamics must occur in short intervals and achieve high coverage in order to maintain proper levels of immunization. on the other hand, the replacement of euthanized dogs by susceptible animals and new individuals entering the reservoir compartment are the main causes of the low effectiveness of the euthanasia of seropositive dogs, a control strategy adopted in brazil against leishmaniasis [ ] . in addition, the population also becomes younger and more likely to acquire other infections under the high turnover regime [ ] . the field of mammal ecology identifies two main reproductive strategies driving population size, each focusing on specific stages of the life cycle. the so-called "slow breeding" animals experience late maturation and their reproductive strategy depends on the survival of juveniles and young adults. on the other hand, "fast breeding" mammals complete their reproductive cycle within their first year of life and place emphasis on fertility as their survival strategy as a species [ , ] . control of the population size of "fast breeding" animals, such as dogs [ ] , is more effectiveness when relying on measures that restrict entry of new individuals into the population as opposed to subjecting animals to euthanasia, a practice that reduces adults' survival. the fast versus slow breeding rationale, the sensitive ethical issues, and the low effectiveness of euthanizing animals observed in regions where this practice has been applied [ , , ] prompted us to only consider sterilization, and not culling, as an alternative control strategy in our study. its use as a population control measure against hydatid disease in developing countries, however, has been recommended [ ] . it is worth noting that in the present study sterilization did not affect the canine population dynamics. after one year and two months, we observed no difference in survival, entrance or recruitment probability between the control region and the intervention area where % of the dogs were sterilized. the impact of sterilization takes place slowly as suggested by modeling exercises. it might take up to five years for the first impact of sterilization to become apparent and up to years of uninterrupted efforts to reach its maximum impact [ ] . reece and chawla [ ] evaluated a program that surgically sterilized , neighborhood dogs in jaipur, india, for eight years and showed that the population declined by only per cent. on the other hand, frank and carlisle-frank [ ] observed only a small impact of a sterilization program on the number of dogs joining a shelter in the united states. amaku et al. [ ] , based on results from a mathematical model developed specifically for stray dogs, concluded that sterilization becomes inefficient in the presence of high abandonment rates, even after prolonged periods of use. natoli et al. [ ] reached the same conclusion after studying for years the impact of a castration and devolution program on a non-restricted cat population. continuous negligent practices of animal ownership, including abandonment, had a negative impact on the sterilization strategy rendering it ineffective and countering the effect of , surgical interventions undertaken in that study. finally, in a study conducted in brazil, dias et al. [ ] concluded that it is counter-productive to invest in sporadic sterilization campaigns of owned dogs, the currently strategy adopted in most of brazilian municipalities. the small impact in controlling the population size, especially in areas with high abandoning rates as in our case, the need to reach high coverage rates without interruptions, the absence of behavioural benefits for castrated dogs [ ] , high costs and null impact on a shortterm perspective, minimize the relevance of sterilization of free-ranging dogs in managing the population and controlling diseases. in this context, it becomes apparent that public health services and non-governmental organizations must develop and prioritize more effective strategies against abandonment practices. in countries where free-ranging dogs are considered a humanitarian or a public health issue the implementation of educational programs addressing responsible animal owning at different levels, the registration of dogs and their owners and the improvement of legislation aimed at those who wish to have a pet becomes imperative [ ] . probability of capture is a useful parameter in the identification of essential population features [ ] . it is known to vary in space, time and among individuals [ ] . although we observed no significant differences in this parameter between genders and areas, it varied over time even in the presence of standardized procedures. such fluctuations may be attributable to social organization features not yet investigated in the population, or to environmental and climatic factors. dias et al. [ ] showed that weather exerts an influence on dogs' activity, and consequently influences the probability of finding a dog in a given capture effort. in our study, even with the vehicles driving around in all the streets of the target regions, there was a large number of animals present but not visualized in all captures. our observations indicate that individual counts based on a census do not adequately estimate the abundance of unrestricted dogs and that the majority of the estimates available in the literature show important biases. different studies aimed at estimating the abundance of free-roaming dogs did not model or even consider the existence of differences in the probabilities of dog detection [ ] . as pointed out before [ ] , counting techniques should be carried out only in short periods of time and when no other alternative becomes available considering logistics, geography and culture of the study region. values of capture probabilities obtained in the present study are similar to those estimated by kalati in a population of urban free-ranging dogs in kathmandu [ ] and may be used as correction factors for the previously published estimates of abundance. in addition to the limitations already mentioned regarding the observation and sampling techniques applied in capture and recapture studies, issues related to the choice of appropriate analytical methodology deserve mentioning. environmental and individual variables, relevant to helping understand the population dynamics [ ] were not included in our models. the logistics of fieldwork turned out to be complex and difficult, requiring the participation of at least six individuals in each capture effort and extensive fieldwork journeys. direct contact with animals was unavoidable since assessing the effectiveness of sterilization was one of the study objectives. studies assessing the population dynamics of dogs, however, could rely on only photographic methods, these being less complex and onerous [ , ] . our choice of modeling procedures for open populations allowed for the estimation of survival and recruitment probabilities of unrestricted dogs. in addition, we tested the data for the statistical assumptions required by each model. model selection followed the aic technique, which compares favorably with the classic statistical and hypothesis testing [ , [ ] [ ] [ ] . lastly, our parameter estimates and confidence intervals express more faithfully the sources of uncertainty present in the whole estimation process, due to the use of the "model averaging" technique. the analytical procedures adopted here addressed methodological limitations of previous publications and propose a new starting point for future studies. in our view, longer periods of observation, larger sample sizes, and the choice of more variable study settings including different social, cultural and geographic characteristics are important topics that need the attention of researchers in the field of unrestricted dogs' ecology. the agenda of the investigation of factors influencing the canine population dynamics must consider the variables addressed in the present study, and further consider the stratification of these population parameters by age groups, as well as by intrinsic animal features and environmental conditions not yet investigated. our estimates of population size in the studied regions in general were small compared to previous estimates in the literature. survival probability was small and probability of animal entry in the population was high during the months period of follow-up. high turnover, attributed mostly to the abandonment of pet dogs, has important implications to the population composition and the control of zoonosis. estimates of survival, recruitment and capture probabilities varied over time. survival and recruitment showed an increasing tendency. mortality patterns did not differ between genders. the probability of entry in the population was higher among males. the observed population dynamics seem to be driven by density-independent factors. sterilization, in turn, had no influence upon the parameters analyzed. our observations are useful for a better understanding of the population dynamics of free-roaming dogs and may aid in the planning, designing and evaluation of population control actions. in this context, it becomes imperative that public health services and nongovernmental organizations develop educational training programs addressing responsible animal ownership and better strategies against abandonment practices. parameter estimates may also be used as input to new predictive mathematical models. even though our study generated important answers and new hypotheses, the scarcity of existent knowledge and the misuse of the proper methodology raise numerous relevant questions yet to be elucidated about the population dynamics of free-roaming dogs. the ecology of stray dogs: a study of free-ranging urban animals a systematic review and 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adoption and low-cost spay/neuter programs merely cause substitution of sources? dynamics and control of stray dog populations management of feral domestic cats in the urban environment of rome (italy) dog and cat management through sterilization: implications for population dynamics and veterinary public policies effects of surgical and chemical sterilization on the behavior of free-roaming male dogs in stray dog and cat laws and enforcement in czech republic and in italy is heterogeneity of catchability in capture-recapture studies a mere sampling artifact or a biologically relevant feature of the population? revisiting the effect of capture heterogeneity on survival estimates in capture-mark-recapture studies: does it matter? size and spatial distribution of stray dog population in the university of são paulo campus, brazil street dog population survey, kathmandu: final report to wsp spot the match-wildlife photo-identification using information theory mark-recapture and mark-resight methods for estimating abundance with remote cameras: a carnivore case study choosing among generalized linear models applied to medical data null hypothesis testing: problems, prevalence, and an alternative model selection in ecology and evolution the authors are grateful for the invaluable support provided by members of staff of the municipal health service and by veterinarians who participated in this study. key: cord- -vhjuus authors: matthews, blake; jokela, jukka; narwani, anita; räsänen, katja; pomati, francesco; altermatt, florian; spaak, piet; robinson, christopher t.; vorburger, christoph title: on biological evolution and environmental solutions date: - - journal: sci total environ doi: . /j.scitotenv. . sha: doc_id: cord_uid: vhjuus drawing insights from multiple disciplines is essential for finding integrative solutions that are required to tackle complex environmental problems. human activities are causing unprecedented influence on global ecosystems, culminating in the loss of species and fundamental changes in the selective environments of organisms across the tree of life. our collective understanding about biological evolution can help identify and mitigate many of the environmental problems in the anthropocene. to this end, we propose a stronger integration of environmental sciences with evolutionary biology. all ecosystems, be they natural or engineered, contain biological organisms that are bound by the principles of biological evolution. as such, biological evolution is often a central feature of many problems that are currently being tackled by environmental scientists. yet fundamental principles from the discipline of evolutionary biology are rarely used in the analysis and mitigation of environmental problems, even when evolutionary processes are closely linked to their manifestation (carroll et al., ; jørgensen et al., ) . environmental scientists are particularly adept at reaching across disciplines to ensure that they have the knowledge and tools necessary to tackle complex environmental problems. here we propose that a wider application of principles of science of the total environment ( ) ⁎ corresponding authors at: eawag, department of aquatic ecology, Überlandstr. , dübendorf, switzerland. url's: blake.matthews@eawag.ch (b. matthews), christoph.vorburger@eawag.ch (c. vorburger). evolutionary biology would help us achieve more sustainable solutions to environmental problems. in brief, evolution is a process of heritable change in the phenotype of a population of organisms (box ). while evolution can result from random genetic drift (representing "neutral" evolution), here we focus on adaptive evolution, defined as a change in population mean fitness in response to natural selection (box ). genetic and trait variation, and how such variation changes over time and space, are fundamental properties of living systems. there is mounting evidence that evolution is sufficiently fast in natural populations to be highly relevant for understanding how populations will respond to human-mediated environmental change (hendry and kinnison, ; hendry, ) . applying evolutionary principles to understand environmental problems is not a novel idea (gunderson and holling, , santamaria and mendez, ) , but widespread application is still limited (jørgensen et al., ) . in the context of the biodiversity crisis ecologists are increasingly using evolutionary theory to help mitigate the https://doi.org/ . /j.scitotenv. . - /© elsevier b.v. all rights reserved. science of the total environment j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / s c i t o t e n v loss of genetic and species diversity due to climate change and environmental pollution (bell and gonzalez, ; kristensen et al., ) . evolutionary theory is also critical to understanding the emergence of antibiotic resistance in microbes (palmer and kishony, ) and chemical resistance in pests (fisher et al., ) . plainly, evolutionary theory can be highly relevant to pertinent environmental problems, but it is not broadly applied. there is a frequent use of methods and technologies originating from evolutionary biology. in particular, molecular genetic methods are often used to characterise microbial community composition (das and dash, ) , and the patterns of gene expression of individual organisms and communities (oziolor et al., ) . while such methods are undeniably useful to gain functional insights, they are rarely used in environmental science to study evolutionary processes. the potential for evolutionary applications in environmental sciences is far reaching, and in the next sections we focus on core concepts of evolution and exemplify how they can be applied to a range of environmental problems in aquatic ecosystems. the structure and rate of change of heritable trait variation in living systems are particularly relevant for understanding environmental problems. living systems are hierarchically structured, where the traits of individuals arise from the interpretation of the environment by genes (so called genotype-phenotype maps; (houle et al., ) ). individuals interact within populations, where average trait values change through evolutionary and environmental processes (burns, ; frank, ; pedersen and tuomi, ) , and populations interact and evolve within multi-species communities (weber et al., ) . as a result of this hierarchical structure, human activities affecting one level of biological organization can have unanticipated outcomes at another level (gunderson and holling, ; melián et al., ) . for example, human activities that affect gene flow among populations can lead to the introduction of either beneficial alleles that help populations adapt to changing environments, or deleterious alleles that contribute to maladaptation of natural populations and thereby can potentially hinder conservation efforts (leitwein et al., ) . despite the long held view that evolution is a slow process, it is now well established that the pace of heritable trait change can be sufficiently fast to affect population dynamics, species interactions, and ecosystem processes -i.e. evolution can act at ecological time scales (hairston et al., ; stockwell et al., ) . the dynamics of species interactions in natural communities are hence not simply a product of past evolution. rather, evolutionary processes can shape trait distributions of populations (i.e. mean and variance) at a pace that is highly relevant for many environmental problems. evolutionary processes can either ameliorate or exacerbate environmental problems. evolutionary adaptation, for example, can drive the recovery of populations, or even multi-species communities, from decline, in a process known as "evolutionary rescue" (bell and gonzalez, ; low-décarie et al., ) . in natural populations, evolution has rescued killifish from chemical pollution (whitehead et al., ) and amphibians from acidification (hangartner et al., ) . in these cases, genetic adaptation has allowed for the persistence of populations in environments that would otherwise be unsuitable. evolutionary novelty can also emerge in populations exposed to synthetic environments created by humans, and, in doing so, perform essential evosystem services (rudman et al., ) . for example, the artificial sweetener acesulfame (ace) is a persistent compound in aquatic environments because it is resistant to microbial-mediated biodegradation both in natural and wastewater treatment environments (kahl et al., ) . recent work suggests that the catabolism of this compound has evolved repeatedly in multiple wastewater treatment plants in germany (kahl et al., ) , possibly associated with a microbial consortium of proteobacterial species (fig. ) . identifying the evolutionary processes governing such bioremediation dynamics could help address the persistence of chemicals in our natural environments for which engineering solutions are lacking. on the other hand, evolutionary processes can also create novel environmental problems, or worsen existing ones. for example, the emergence and amplification of antibiotic resistance genes is a global problem, caused by the widespread overuse of antibiotics (palmer and kishony, ) . in wastewater treatment plants, the concentration of antibiotic resistance genes may be amplified by evolution prior to water discharge into natural aquatic environments (ju et al., ) (fig. ). understanding and monitoring the evolutionary process in wastewater treatment plants could improve our ability to limit the release of antibiotic resistance genes into natural environments (czekalski et al., ) . in this section, we illustrate how a broader application of evolutionary theory can enable environmental scientists to craft better solutions for environmental problems. to this end, we use four examples from aquatic systems: (i) emergence and epidemiology of disease, (ii) renewable production of biofuels, (iii) chemical pollution, and (iv) outbreaks of algal blooms. diseases are among the most severe environmental problems. they are a threat to biodiversity (fisher et al., ; lips et al., ) , to food production (strange and scott, ) and to human health (jones et al., ) . disease outbreaks are often caused by pathogens that have undergone a recent host shift or expansion of their geographic range (engering et al., ; longdon et al., ) . most disease-causing organisms have large populations and short generation times, which generally facilitates rapid evolution. consequently, disease emergence typically involves rapid co-evolutionary dynamics that stem from natural selection on both pathogen infectivity and host defense (penczykowski et al., ) . rapid evolutionary dynamics are expected to take place at the onset of disease emergence, governed by the pathogens' and the hosts' evolutionary history. disease emergence is often a consequence of human activities. transport between continents can bring pathogens into naïve host populations that are, at least initially, defenseless; they can lack sufficient genetic variation for resistance because they do not have coevolutionary history with these pathogens. the crayfish plague provides a good example. aphanomyces astaci, a pathogen of freshwater crayfish native to north america came to europe with introduced american crayfish (svoboda et al., ) . american crayfish species had evolved a high tolerance of the pathogen, due to their long evolutionary history, but the pathogen proved devastating to stocks of european freshwater crayfish species (holdich et al., ) . likewise, human activities that modify ecosystems for food production can promote the emergence of locally highly virulent pathogens (stukenbrock and mcdonald, ) . for example, large monocultures of genetically homogenous plants can facilitate the evolution of host specialization (mcdonald and stukenbrock, ) , leading to evolutionary dynamics that are not commonly observed in natural ecosystems. evolutionary theory can be instrumental in helping to understand the origin and spread of diseases through populations. increasingly, researchers can track disease dynamics over time by comparing genetic variation among isolates, and such data can help inform policy decision and management of viral diseases, such as covid- (andersen et al., , brüssow, and ebola (mbala-kingebeni et al., ) . drug treatment is often the default approach used to control emergent bacterial and fungal diseases, but in some cases a single new drug can cause strong natural selection, and, combined with the high evolutionary potential of pathogens, this means that the expected time until drug resistance evolves can be short (fisher et al., ; kennedy and read, ) . for such scenarios, we need to develop evolution-aware strategies to avoid and control emergent diseases. for example, in the case of chemical treatments, combination therapy or the sequential application of different drugs can delay resistance evolution (palmer and kishony, ; roemhild et al., ) , and the development of 'evolution-proof' drugs is a particularly attractive idea (bell and maclean, ) . alternative strategies include fighting the disease with agents that are able to evolve themselves, such as microbial symbionts that provide protection against the disease (kueneman et al., ) . the dwindling supply and the negative environmental impact of fossil fuels have spurred substantial research and investment into using biofuels as a renewable and sustainable source of energy (sheehan et al., ) . among the many potential sources of biomass for biofuels, phytoplankton or "algal" biofuels are among the most efficient in terms of land-use and energy production per unit biomass (y. chisti, ; yusuf chisti, ) . until now, algal biomass production for biofuel has heavily focused on the production of single species with desirable properties, namely high lipid content, fast growth rates, and resistance to disease and grazers. however, farming monocultures is notoriously difficult because individual species or strains, be they algae or crops, can never possess all of the desirable traits for long-term stable crop production at high yields (smith et al., ) . the ideal species for maximum production would be unconstrained by the trade-offs inherent to all living systems. yet such omnipotent organisms, known in evolutionary biology as darwinian demons (krakauer, ; law, ) , do not exist and cannot be engineered. nevertheless, sustainable yield of biofuels could be optimized by understanding the biochemical and biophysical basis of the fundamental trade-offs between growth rate, lipid production and traits that make better competitors, confer resistance to parasites, and are resistant to grazers (shurin et al., (shurin et al., , ; t. yoshida et al., ) . understanding the evolution of ecologically relevant traits, under different biotic and abiotic contexts, may improve the stability and efficiency of biofuel production. the application of evolutionary theory to algal biofuel production is in its infancy, but holds immense potential. algal populations are large and have short generation times. usually the populations maintain high phenotypic and genetic diversity (brandenburg et al., ; chen and rynearson, ; lebret et al., ; masseret et al., ; rynearson and armbrust, ) . evolution in such populations can be fast if selection is strong (thibodeau et al., ; takehito yoshida et al., ) . harnessing the adaptive evolutionary potential of algal populations could help us explore the range of feasible trait space to obtain desirable trait combinations. for example, researchers are currently trying to simultaneously improve the yield of triacylglycerols in culture (used to produce fatty acid methyl esters needed used in biodiesel production), while concurrently maximizing population growth rates. such trait combinations are normally mutually exclusive. approaches include genetic engineering (zeng et al., ) , directed evolution via successive rounds of mutagenesis and selection (johnson et al., ; lewin et al., ) , and selection on the existing levels of genetic variation in a population (mooij et al., ; shurin et al., ) . while evolution might help us improve biofuel production (kazamia et al., ) , it might also culminate in undesirable outcomes. for example, engineering solutions based on evolutionary trade-offs might be eroded over time due to mutation, horizontal gene transfer, and recombination. custom designed biofuel production systems should also consider the evolutionary consequences of rapid harvesting. for example, rare beneficial mutations arising during population expansion, might be periodically lost before they sweep to dominance in the populations (bull and collins, ; shurin et al., ) . in short, evolution offers both promises and pitfalls for biofuel production. chemical pollution is a global problem with a local character (grimm et al., ; halpern et al., ; vörösmarty et al., ) . chemical pollution often stems from chemical pest control applied in agricultural production, as well as from the unwanted waste produced by human population growth and industrial activities. wastewater treatment plants can only remove and target compounds that pass through the sewage system; many other compounds still enter the natural environment in a diffuse manner, especially from agriculture. these chemical compounds can have toxic effects on individual organisms and these effects can be enhanced when they occur in mixtures (abdelghani et al., ; connon et al., ) . for instance, pest control requires highly biologically active substances to target unwanted algae, fungi and arthropods. when pesticides then leak into ecosystems that are not the target of the application, this can change food web structure and influence ecosystem function (stamm et al., ) . because pollution and the ecological context in which pollution occurs is often highly local, we can expect pollution to have many different evolutionary consequences in natural ecosystems. however, the biological effects of pollutants are typically studied using a limited number of model species and strains, usually in oversimplified ecological contexts that might underestimate their effects in nature (relyea and hoverman, ) . furthermore, many of the approaches used in environmental science and ecotoxicology to assess the environmental effects of pollutants only test a few selected genetic lineages of organisms (e.g., single strains of daphnia), and often ignore both within-population variation in sensitivity to pollutants and the effects of mixtures of pollutants on organisms. for example, morphologically similar but genetically distinct lineages of amphipods, within the gammarus fossarum cryptic species complex, vary in their sensitivity to the fungicide tebuconazole and the insecticide thiacloprid (feckler et al., ) . such lineage diversity within species is rarely accounted for in typical assessments of pollutants on organisms (relyea and hoverman, ) . synthetic chemicals present a particular challenge because the exposed organisms may lack the exposure history necessary for the emergence of an evolutionary adaptation. synthetic chemicals can also act as mutagens that disrupt the homeostasis of organisms (bickham et al., ) . chemical toxicity can rapidly drive populations to such small sizes that their persistence over time becomes threatened (williams and oleksiak, ) . interestingly many classic studies about rapid evolution involve chemical pollution, such as the evolution of resistance to pesticides, resistance to antibiotics or mining-related metal pollution (hoffmann and parsons, ; palumbi, ) and, more recently, pollutant induced elevated mutation rates and rapid adaptation (brady et al., ; coutellec and barata, ; kimberly and salice, ; loria et al., ; palumbi, ) . evolutionary adaptation to chemical pollution can also rescue populations from extinction caused by demographic decline. for example, experimental daphnia populations that were initially highly sensitive to metal contamination recovered rapidly via genetic adaptation (hochmuth et al., ) . in another example, natural killifish populations inhabiting urban estuaries adapted to lethal levels of pollutants with genetic adaptations (oziolor et al., ; reid et al., ) . unsurprisingly, adaptation of a population can also be an unwanted outcome of management, such as when the evolution of resistance reduces the sensitivity of a species used in ecological risk assessment (morgan et al., ) . evolution's ability to alter the direction of responses to environmental change, such as that brought by chemical pollution, is one of the main arguments for including evolutionary concepts in environmental research. finally, potential for evolutionarily based solutions to pollution comes from implementing bioremediation, such as designing microbial communities that have evolved the ability of biodegradation of chemicals (liu and suflita, ) . harmful algal blooms are often associated with eutrophication, pollution and climate change (huisman et al., ; monchamp et al., ) . harmful algal blooms, which can persist for weeks or months, may foul drinking water, turn lakes anoxic and kill fish, and render lakes unacceptable for recreational use (lewitus et al., ; paerl et al., ) . ecological theory suggests that blooms develop when nutrient input releases phytoplankton from control by grazers (abrams and walters, ; gragnani et al., ; pančić and kiørboe, ) . additionally, evolutionary processes are also relevant to the emergence, volume and toxicity of blooms. indeed, we postulate that trying to manage harmful blooms without darwin, is like trying to fly to the moon without newton (modifying andrew read's concluding remark on his tedmed talk on importance of evolutionary medicine: https://www. tedmed.com/talks/show?id= ). the trade-off between resource uptake and grazing resistance is at the root of the ecological and evolutionary causes of bloom biomass (cloern, ) . selective grazing by zooplankton will deplete edible algae and, subsequently, increase the abundance of well-defended algae (hairston et al., ; takehito yoshida et al., ) . harmful algal blooms are characterised by an array of defense traits that are favored by natural selection. some algae produce compounds that are toxic to grazers, such as the neurotoxins, saxitoxins and domoic acid produced by dinoflagellates, cyanobacteria, and diatoms, respectively (pančić and kiørboe, ; xu and kiørboe, ) . remarkably, toxin production varies widely both within and among populations. for example, some lineages entirely lack the genes for toxin production (brandenburg et al., ; briand et al., ). the evolutionary dynamics of different toxic/non-toxic genotypes during algal blooms is likely driven by physiological trade-offs between costs of toxin production and resource uptake for growth (brandenburg et al., ; cadier et al., ; chakraborty et al., ; kiørboe and andersen, ) . such defense-growth trade-offs are likely important for the emergence of harmful algal blooms (burford et al., ; jankowiak et al., ; kim et al., ; li et al., ) , but the selective factors that favor toxic variants in bloom forming algae are not fully understood. identifying the evolutionary processes involved in algal blooms would likely help us predict which algal blooms might turn toxic. in a first step, reliable prediction would enable the avoidance of risks associated with toxic algal blooms (e.g. by timely establishment of exclusion zones), and in a second step, it could inform mitigation measures to reduce the occurrence of algal blooms (e.g. by influencing relevant selective forces such as nutrient input). evolutionary processes are often an inescapable and critical component of both understanding and solving environmental problems. the evolution of resistance genes will continually challenge our efforts to halt diseases through the development of new drugs, highlighting the need to complement efforts in drug discovery with the development of evolution-aware application strategies. a better appreciation of evolution's limits and, in particular, the impossibility of darwinian demons, is critical to meeting our energy demands by matching algal genotypes with optimal environmental conditions for biofuel production. in a similar vein, choosing strains that have evolved tolerance to pollutants might help sustain populations in deteriorating environments, while strains naive to pollution might be a more conservative option when assessing ecological risk to chemical pollutants. engineering solutions in waste-water treatment plants might be improved if we could harness evolution's power to help biodegrade persistent compounds (brenner et al., ) . other environmental problems with limited engineering-oriented solutions could be tackled with evolutionary perspectives. for example, biocides may be applied to combat algal blooms, but it is notoriously difficult to predict the timing, duration and toxicity of algal blooms. a better understanding of the evolutionary dynamics of such systems, gained, for example, by tracking environmental change in real-time and linking those changes with environmental sources of natural selection, could help us predict the outbreaks of toxic algae. indeed, there is a growing need in many areas of environmental science to efficiently forecast ecosystem change across natural and human-induced gradients (petchey et al., ) and to understand the consequences of such changes for ecosystem (and evosystem) services (costanza et al., ; rudman et al., ) . this is particularly relevant for ecosystems that provide vital services to society, but are also sensitive to anthropogenic impacts. predictions about complex ecological systems are challenging and require solid understanding of ecological and evolutionary mechanisms behind population growth, genetic and trait diversity, trait-environmental relationships, trade-offs, and community dynamics. such principles are present in the environmental science literature, but are only sporadically applied to solve environmental issues. it is possible that prevailing misconceptions about the pace and prevalence of evolution may be blocking the integration of evolution into the environmental sciences. first, the pace of evolutionary adaptation is not only set by the rate of mutations and the subsequent rate of increase of novel alleles in the population. instead, the rate of adaptation, i.e. the increase in mean population fitness over time, is directly proportional to the genetic variance in a population that can respond to natural selection (fisher, ) . evolution from existing levels of heritable trait variation in a population can be much quicker and more predictable than expected based on evolution driven via new variants in the population that arise solely by mutation. second, evolution is neither rare nor a special case. the challenge for environmental science is to determine the relative importance of evolution, either for causing or for ameliorating a particular environmental problem. overall, we argue that evolutionary principles are a useful resource for coming up with solutions to environmental problems. on the one hand, seemingly rational solutions might require some 'evolution proofing' to effectively anticipate and limit any potential negative impacts of evolution on the expected outcomes of our interventions. on the other hand, evolution itself can be a powerful design strategy for solving environmental problems. design by directed evolution, for example, has made considerable progress developing novel enzymes (arnold, ) , and configuring communities to perform specific functions that improve environmental conditions (ghoul and mitri, ) . natural selection is a powerful force that can efficiently explore the the four forces of evolution. mutations are random, heritable changes in the sequence or structure of a gene. they include substitutions of individual bases in the dna sequence, insertions and deletions of dna fragments, and structural rearrangements of chromosomes. new variants of the same gene generated by mutation are referred to as alleles. mutations can be neutral, meaning they do not affect the phenotype of their carrier, advantageous in specific environments, meaning they affect the phenotype such that it increases survival and/or reproduction, i.e. fitness, or deleterious in specific environments. for example, a mutation that confers resistance to a pesticide may be beneficial in an environment where the pesticide is present but detrimental in an environment where the pesticide is absent. mutations are the ultimate source of genetic variation and provide the original resource for adaptive evolution and biological innovation. natural selection is the process of unequal survival and reproduction among individuals due to differences in phenotype. some individuals of the population are more likely to survive and reproduce because they have trait combinations that make them better at coping with the current environment than other individuals. assuming that the phenotypic traits under selection are heritable, i.e. trait values are transmitted across generations, the favorable traits, which represent 'good genes', will be passed to the offspring. in this way, the frequency of the 'good' gene variants will increase in the population, leading to evolutionary adaptation. gene flow gene flow is the exchange of genetic material between populations. it occurs when individuals or their gametes migrate into a new population and reproduce. gene flow can bring new alleles (i.e. genetic variants) into the receiving population and thereby influence the potential for this population to evolve. gene flow can be maladaptive, and reduce the fitness of the local population, or adaptive. if migration is sufficiently high and migrant genes are not selected against, gene flow will homogenize allele frequencies and reduce genetic differences in the genetic composition of populations. genetic drift is the stochastic change in allele frequencies over generations. it occurs because allele frequencies in populations can deviate by chance from those of the parental generation, due to the random sampling of gametes. it affects particularly small populations. it can lead to the loss of genetic variation and the accumulation of deleterious mutations and, as a result, constrain a population's adaptation to changing environmental conditions. combinatorial trait space that organisms could theoretically occupy. the trait space of living systems is replete with opportunities to solve environmental problems, and natural selection might often outpace our own ability to find these solutions. perhaps a way forward is to relinquish our engineering hubris in favor 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pollution: key principles, and lessons from rapid repeated adaptation of killifish (fundulus heteroclitus) populations signatures of selection in natural populations adapted to chronic pollution toxic dinoflagellates produce true grazer deterrents rapid evolution drives ecological dynamics in a predator-prey system evolutionary trade-off between defence against grazing and competitive ability in a simple unicellular alga, chlorella vulgaris microalgae bioengineering: from co fixation to biofuel production this manuscript was supported by internal eawag funds and an swiss national science foundation [grant number a_ ] to bm. we thank arianne maniglia, and gioia matheson for help in organising the workshop that supported this project, and paula ramsay for editing. key: cord- -heoj ji authors: hubbard, amelia; lewis, clare m; yoshida, kentaro; ramirez-gonzalez, ricardo h; de vallavieille-pope, claude; thomas, jane; kamoun, sophien; bayles, rosemary; uauy, cristobal; saunders, diane go title: field pathogenomics reveals the emergence of a diverse wheat yellow rust population date: - - journal: genome biol doi: . /s - - - sha: doc_id: cord_uid: heoj ji background: emerging and re-emerging pathogens imperil public health and global food security. responding to these threats requires improved surveillance and diagnostic systems. despite their potential, genomic tools have not been readily applied to emerging or re-emerging plant pathogens such as the wheat yellow (stripe) rust pathogen puccinia striiformis f. sp. tritici (pst). this is due largely to the obligate parasitic nature of pst, as culturing pst isolates for dna extraction remains slow and tedious. results: to counteract the limitations associated with culturing pst, we developed and applied a field pathogenomics approach by transcriptome sequencing infected wheat leaves collected from the field in . this enabled us to rapidly gain insights into this emerging pathogen population. we found that the pst population across the united kingdom (uk) underwent a major shift in recent years. population genetic structure analyses revealed four distinct lineages that correlated to the phenotypic groups determined through traditional pathology-based virulence assays. furthermore, the genetic diversity between members of a single population cluster for all pst field samples was much higher than that displayed by historical uk isolates, revealing a more diverse population of pst. conclusions: our field pathogenomics approach uncovered a dramatic shift in the pst population in the uk, likely due to a recent introduction of a diverse set of exotic pst lineages. the methodology described herein accelerates genetic analysis of pathogen populations and circumvents the difficulties associated with obligate plant pathogens. in principle, this strategy can be widely applied to a variety of plant pathogens. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. results: to counteract the limitations associated with culturing pst, we developed and applied a field pathogenomics approach by transcriptome sequencing infected wheat leaves collected from the field in . this enabled us to rapidly gain insights into this emerging pathogen population. we found that the pst population across the united kingdom (uk) underwent a major shift in recent years. population genetic structure analyses revealed four distinct lineages that correlated to the phenotypic groups determined through traditional pathology-based virulence assays. furthermore, the genetic diversity between members of a single population cluster for all pst field samples was much higher than that displayed by historical uk isolates, revealing a more diverse population of pst. conclusions: our field pathogenomics approach uncovered a dramatic shift in the pst population in the uk, likely due to a recent introduction of a diverse set of exotic pst lineages. the methodology described herein accelerates genetic analysis of pathogen populations and circumvents the difficulties associated with obligate plant pathogens. in principle, this strategy can be widely applied to a variety of plant pathogens. emerging and re-emerging diseases of humans, animals and plants pose a significant hazard to public health and food security. these threats can arise from newly discovered pathogens, such as the middle east respiratory syndrome (mers) coronavirus in humans [ ] , or novel host adaptation, as in zoonotic influenza [ ] . recent disease outbreaks in plants have been associated with expansions of pathogen geographic distribution and increased virulence of known pathogens, such as in the european outbreak of ash dieback [ ] and wheat stem rust across africa and the middle east [ ] . independent of the host organism, the scale and frequency of emerging diseases have increased with the globalization and industrialization of food production systems [ ] . improved surveillance mechanisms and diagnostic tools are needed to rapidly respond to these emerging threats. with recent advances in dna and rna sequencing, bacteriologists and virologists are capitalizing on these technological advances by integrating high-resolution genotypic data into pathogen surveillance activities [ ] . however, the application of genomics to emerging filamentous plant pathogens has lagged. filamentous plant pathogens tend to have large genomes and are often obligate parasites that cannot be axenically cultured in the laboratory. the time-consuming and tedious protocols required to maintain these pathogens on their hosts have impeded the translation of genomic technologies into surveillance and diagnostics methods. traditional diagnostic tools for pathogens have been based on targeted cultures, pcr-based approaches and/ or phenotypic evaluation of disease response in specific plant genotypes [ ] . these methods detect only known pathogenic agents, can introduce bias, and can fail to recognize novel variants or races due to their narrow scope [ ] . however, next-generation sequencing technologies can circumvent these limitations to provide a rich source of data for the development of surveillance and diagnostic tools. the high resolution of these approaches also enables exploration of the genetic determinants underpinning pathogenicity. whole-genome sequencing has emerged as a preferred technology, especially for viruses with relatively small genomes (approximately kb on average) [ ] , although this methodology is less tractable in pathogens with large genomes such as filamentous plant pathogens, which have genomes that range from to mb [ ] . alternatively, rna sequencing (rna-seq), which focuses solely on the expressed fraction of the genome, reduces the sequence space of the sample and provides relevant transcriptome data for both the pathogen and host in situ [ ] . despite modern agricultural practices, diseases of the major food crops cause up to % pre-harvest yield loss [ ] . among these crops, wheat is a critical staple providing % of the calories and over % of the protein consumed by humans [ ] . one of the major fungal diseases of wheat is yellow (stripe) rust caused by the obligate fungus puccinia striiformis westend. f. sp. tritici eriks (pst) [ ] . this disease is widespread across the major wheat-producing areas of the world and can cause significant reductions in both grain quality and yield in susceptible cultivars [ ] . in the past decade, new pst races have emerged that are capable of adapting to warmer temperatures, have expanded virulence profiles, and are more aggressive than previously characterized races [ ] . more recently, a series of pst races have arisen in europe and overcome many of the major resistance genes in european germplasm [ ] . for instance, in a race group collectively called 'warrior' (based on the virulence of one of the initial variants of this group to the uk wheat variety warrior) emerged as a serious threat to wheat production. however, the origin of this new race and its relationship with previously characterized races remain unclear. an important first step towards the development of more effective surveillance and diagnostic tools is the availability of a draft reference genome and annotation. cantu et al. [ ] published a first draft sequence of pst isolate (pst- ) with , annotated proteincoding sequences across the . mb assembly. more recently, zheng et al. [ ] published a mb draft sequence of chinese pst isolate cyr using a 'fosmidto-fosmid' approach and annotated , proteincoding sequences. these genomic resources can be used to identify pathogenicity determinants, such as secreted effector proteins [ ] that are recognized in certain host genotypes, where they induce an immune response that prevents disease progression. avirulence effector proteins are under strong selective pressure to adapt in order to evade detection by the host plant immune system [ ] . the signatures of adaptation and gene expression patterns of pathogen isolates with distinct virulence profiles can provide a powerful means of identifying specific avirulence/virulence proteins that can be used to track pathotypes at a national and international level. furthermore, publication of these draft reference genomes also provides an opportunity to characterize pathogen populations at a considerably higher resolution and on a much wider scale through re-sequencing of pst isolates. in this study, we developed a robust and rapid 'field pathogenomics' strategy, using transcriptome sequencing of pst-infected wheat leaves to gain insight into the population structure of an emerging pathogen. our analysis uncovered a dramatic shift in the pst population in the uk and supports the hypothesis that recent introduction of a diverse set of exotic pst lineages may have displaced the previous pst populations. our field pathogenomics approach circumvents the difficulties associated with less-tractable filamentous plant pathogens and can be applied to other emerging populations of pathogens. genotyping pathogens and their hosts using rna-seq of field-collected infected leaves to characterize the genotypic diversity of pst at the field level, we collected samples of wheat and triticale infected with pst from different counties across the uk in the spring and summer of ( figure a ; table s in additional file ). from these, we selected pst-infected wheat samples from wheat varieties that spanned the resistance spectrum, and pst-infected triticale samples (table s in additional file ). total rna was extracted from each sample and subjected to rna-seq analysis ( figure a ). after filtering, an average of % (standard deviation . %) reads aligned to the pst- reference genome [ ] , indicating that fungal transcripts account for a high percentage of the transcripts in pst-infected plant tissue (table s in additional file ). to address whether each sample comprised a single pst genotype without considerable bias in allelespecific expression, we calculated the distribution of read counts for biallelic single nucleotide polymorphisms (snps), determined from alignment to the pst- genome. as a dikaryon, the pst mean of read counts at heterokaryotic positions is expected to have a single mode at . , with two alternative alleles each representing one of the two haploid nuclei (additional file ) [ ] . based on the presence of only two alleles and the shape of the distribution being comparable to purified isolates when heterokaryotic snps were considered, we concluded that all samples likely represent a predominantly single genotype with little bias in allele expression (additional files and ). we next used our data to confirm the wheat variety in a particular pst-infected sample. to this end, we extracted the wheat sequences flanking a set of , genetically mapped wheat snps (table s in additional file ) [ ] . nine of the pst-infected wheat samples were collected from wheat varieties with identified snps (donal o'sullivan (university of reading) and james cockram (niab), personal communication) and for each of these samples, reads were independently aligned against the wheat sequences extracted above. each of the , snp positions with ≥ × coverage was then assessed for correlation against the available sequence data for seven wheat varieties. this analysis confirmed the wheat variety recorded at the point of sample collection as the most likely variety for all nine pst-infected wheat samples ( figure ). furthermore, for samples taken from the wheat variety oakley, the second highest matching variety was kws santiago, whose parents are sherbourne and oakley. oakley has been used widely in the parentage of various wheat varieties as reflected by the level of similarity between pst-infected oakley samples and all other varieties ( figure ). this analysis demonstrates that the transcriptomic data from pst-infected field samples can be used successfully to determine the host wheat variety. transcriptome sequencing was carried out on samples to generate transcript data from both the pathogen and host. for the pathogen, the data were used to assess the pathogen population diversity and differential gene expression. for the host, the data were used to confirm the host variety within a particular sample. snp, single nucleotide polymorphism. (b) field isolates (dark blue squares) are distinct and highly diverse when compared with the older uk population (light blue squares). phylogenetic analysis was undertaken using the third codon position of , pst- gene models ( , , sites) with ≥ % breadth of coverage for all pst isolates using a maximum likelihood model. stars indicate samples in which both the genome and transcriptome were sequenced from the same pst isolate. to determine the relationship between the pst field isolates and previously prevalent pst populations, the genomes of uk and french purified pst isolates collected between and were sequenced using an illumina whole-genome shotgun approach figure identification of wheat varieties using transcriptome data generated directly from pst-infected field samples. a total of , snp positions were used to differentiate wheat varieties. each of the , snp positions with ≥ × coverage was assessed for correlation against the available sequence data for seven wheat varieties. for each snp position, if the pst-infected field sample matched the sequence at a snp site for a particular variety (for example, variety = aa; field sample = aa) the position was scored , if the site only partially matched (for example, variety = aa; field sample = ac) then the position was scored . , and if the site had no match (for example, variety = aa; field sample = cc) then the position was given a score of . for each sample, the total score was determined and visualized for each of the seven wheat varieties. numbers in parentheses represent scores associated with differential markers for a particular wheat variety (blue shading). monomorphic markers across all varieties are represented in red. background colour and header relate to the reported variety for a given sample. warrior- , w ; warrior- , w . ( table s in additional file ). after filtering, reads were independently aligned to the pst- reference genome. phylogenetic analysis was undertaken using the third codon position of , pst- gene models ( , , sites) with ≥ % breadth of coverage for all pst isolates using a maximum likelihood model. this analysis illustrated that of the historical uk pst isolates and all french isolates clustered together in a single clade with little genetic variation (figure b) . by contrast, the pst field isolates collected in were distantly related to the older uk population, and included several diverse lineages. furthermore, a subset of of the pst field isolates were also genetically similar to a characterized 'warrior' type pst isolate from (pst- / ; figure b) . this indicates that a diverse pst population that contained the 'warrior' pathotype was prevalent across the uk in . with the first record of the 'warrior' pathotype occurring in the uk in , we decided to investigate the distribution of this lineage further by sequencing the genome of two purified pst isolates with known virulence profiles from and two from [ ] . after filtering, reads were aligned to the pst- reference genome. phylogenetic analysis revealed that two pst isolates from (pst- / and pst- / ) were more closely related to the older uk population, whereas the remaining isolates clustered within the 'warrior' type lineage ( figure b) . to further support the topology of the phylogenetic tree, we extracted rna from a susceptible wheat variety infected independently with six pst isolates (pst- / , pst- / , pst- / , pst- / , pst- / and pst- / ) that were also subjected to genome sequencing. the distribution of biallelic snps, from alignment to the pst- genome, confirmed that each sample comprised predominantly a single pst genotype without considerable bias in allelespecific expression (additional file ). when snp sites with sufficient depth of coverage in both the genomic and rna-seq samples were compared, an average of . % were identical between the genomic and rnaseq datasets (table s in additional file ). this indicates that allele-specific gene expression had a negligible effect on the topology of the phylogenetic tree. this analysis further supports the recent emergence of a diverse pst population that may have now displaced the previous pst population in the uk. to elucidate the population structure among the pst uk field isolates, we generated a list of , synonymous snp sites, of which , were biallelic. we used multivariate discriminant analysis of principal components (dapc) with the , biallelic snp sites to define the population structure and identify groups of genetically related pst isolates. the bayesian information criterion supported the division of pst isolates into four population clusters, which were clearly distinct in a scatterplot of the five principal components of the dapc (figure a ,b). in addition, bayesian-based clustering of the full set of , synonymous snp sites using the program structure classified the pst isolates into four population clusters (figure c ,d) that differed only in the partitioning of two isolates (pst- / and pst- / ) compared with the dapc assignment (additional file ). phylogenetic analyses were also undertaken using the third codon position of , genes ( , , sites) with ≥ % breadth of coverage for all pst isolates using a maximum likelihood model. this analysis supported the assignment of pst isolates to the four population clusters as reported by the bayesian-based clustering method ( figure d ). cluster-specific snps were converted into pcr-based assays and shown to differentiate the pst lineages (table s in additional file ; additional file ). furthermore, within the pst field samples collected in , all pst isolates sampled from triticale clustered within a single genetically distinct lineage ( figure d , cluster ii), potentially indicating a degree of host specificity within the pst population in the uk. next, to determine if the observed population structure was reflected in the phenotypic characteristics of the pst field isolates, we purified and cultured a subset of isolates for virulence profiling. four pst isolates from each of the three population clusters derived from pst-infected wheat samples were inoculated on a series of differential wheat varieties. disease severity was recorded to days post-inoculation (table s in additional file ). phylogenetic analysis of the pst isolates using a maximum likelihood model ( , genes; , , sites) was combined with their virulence profiles to assess correlations between the population substructure and pathology data. this analysis revealed distinct phenotypic characteristics for each population cluster that were different from members of other population clusters, but were largely conserved between isolates of a similar genetic background ( figure a ). furthermore, principal component analysis of the phenotypic characteristics supported the clear division of the isolates into three phenotypic groups that correlated directly with the genetic population clusters (figure b ). this reflects a clear association between the genotypic and phenotypic diversity displayed by the pst field isolates. cluster i isolates displayed the least phenotypic diversity between pst isolates. this correlated with much lower nucleotide diversity between members of this cluster compared with other clusters (figure c) . overall, however, the degree of genetic diversity between members of a single population cluster for all pst field samples was much higher than that displayed by the older uk and french isolates collected between and , excluding pst- / (figure c ). substantial genetic differentiation was also identified in all pair-wise comparisons of the four population clusters, with f st values ranging from . to . (figure c ). the variation in gene expression between members of a population cluster did not influence the calculation of genetic diversity (additional files and ). taken together, this supports the hypothesis that the new uk pst population is derived from a highly diverse founder population. polymorphic and differentially expressed effector candidates can be linked to the virulence profiles of the pst field isolates we also used our field pathogenomics approach to look for two signatures of adaptation, namely mutation and differential gene expression, by treating all isolates within a population cluster as replicates in the analysis. specifically, we sought to identify potential effector proteins and link these to the distinct virulence profiles within the pst population. first, to identify polymorphic effector candidates, we discriminated , homokaryotic and heterokaryotic snp sites that induced non-synonymous substitutions from alignment of all pst field isolates against the pst- reference genome. of these non-synonymous sites, we identified , snp sites where the amino acid residue was conserved among all members of a single population cluster with coverage in the region, but differed from the amino acid encoded by all members from at least one other population cluster (table s in additional file ). these , snp sites figure the pst field isolates are highly diverse and group genetically into four distinct population clusters. (a) scatterplot using the first two principal components (y-axis and x-axis, respectively) of the discriminant analysis of principal components (dapc) analysis of , synonymous single nucleotide polymorphism (snp) sites. each symbol represents a single pst isolate, coloured according to assignment to one of four population clusters. all four population clusters are clearly separated by dapc analysis. (b) the first three eigenvalue components from the dapc analysis, supporting the maintenance of three discriminant functions in the dapc analysis. (c) the optimal predicted number of population clusters k for the dataset is four. the y-axis corresponds to the bayesian information criterion (bic), a goodness-of-fit measurement calculated for each k. the elbow in the bic values (k = ) indicates the optimal number of populations. (d) phylogenetic analysis using a maximum likelihood model ( , , sites) and bayesian-based clustering of , synonymous snp sites classified pst field isolates into four population clusters. all pst isolates sampled from triticale clustered within a single genetically distinct lineage, cluster ii. bar charts represent structure analysis, with each bar representing estimated membership fractions for each individual. stars highlight isolates purified for virulence profiling. coloured circles represent uk counties in which samples were collected (table s in additional file ). were dispersed among , genes that displayed clusterspecific unique amino acid substitutions, of which had detectable secretion signals (figure a ). using the most highly ranked pst effector candidates from our previous study [ ] , we identified genes that encoded cluster-specific polymorphic proteins that displayed features typical of characterized effector proteins ( figure a ). next, to assess whether the gene expression profiles of the pst field isolates could be associated with cluster-specific disparity in virulence profiles, reads from each isolate were aligned independently to the pst- genome. differential expression analysis was conducted after normalization to identify genes that were significantly differentially regulated between the four population clusters (false discovery rate < . ; p-value < . ). all isolates within each population cluster were used as replicates in the analysis (table s in additional file ; additional file ). of the genes that were identified as significantly down-and up-regulated for all isolates within a particular population cluster, between . and . % could be annotated with potential structural or enzymatic functions (figure b ; additional file ). of those that were not annotated, an average of . % (standard deviation . %) were predicted to encode proteins with detectable secretion signals (figure b) . furthermore, we identified up-regulated and down-regulated genes that were among the most highly ranked pst effector candidates from our previous study (figure b) . one of these candidates, pst _ , was significantly down-regulated by isolates in cluster iii and had two amino acid substitutions that were specific and conserved among cluster i isolates (figure c ; additional file ). exploiting transcriptome sequencing for surveillance and population analysis of (re)-emerging pathogens human, animal and plant pathogens necessitate constant monitoring to preserve public health and food security. with the advent of next-generation sequencing technologies, it is now possible to integrate high-resolution dna and rna sequencing into pathogen surveillance programs. however, many pathogens cannot be axenically cultured, limiting access to pure dna and rna preparations. furthermore, large-scale population analysis of fungal pathogens by whole-genome sequencing remains limited by the lengthy processes associated with purification and multiplication of isolates for high molecular weight dna extraction and the cost of sequencing large genomes. we have developed an approach for pathogen population surveillance based on high-resolution transcriptome data acquired directly from field samples of pathogen-infected wheat and triticale. even though the analyzed samples consist of a mixture of pathogen and host rna, we recovered enough pathogen sequences for analysis. also, the rna-seq data were deep enough for reliable genotypic characterization. similar approaches using shotgun genome sequencing could have been problematic due to the large size of the genome of wheat (approximately gb) compared with that of pst (approximately mb) [ , ] . our approach also captures the pst population directly from the field and negates any biases that might be caused by purification and multiplication of the pathogen in the laboratory, a lengthy process that can impose artificial selection on the pathogen. using field pathogenomics, we could detect only a single pst genotype within each lesion. furthermore, using comparative analysis of rna-seq and genomic sequence data from six independent pst isolates (pst- / , pst- / , pst- / , pst- / , pst- / and pst- / ), we were able to confirm that allelicspecific expression between the two pst nuclei had minimal effect on genotypic analysis. together these results demonstrate that rna-seq analysis of pst-infected plant material is a useful approach for accurately genotyping isolates of pst directly from the field. however, our findings contrast with studies of mycosphaerella graminicola on wheat and rhynchosporium secalis on barley, where co-infection with multiple genotypes is common [ , ] . analyses of field pathogenomics data may be more complex in such pathosystems. whilst effectively capturing pathogen diversity, transcriptome sequencing of infected host tissue can also be leveraged to assess the genotype of the host. the (c) pst _ is a previously identified effector candidate that was significantly down-regulated by isolates in cluster iii and had two amino acid substitutions that were specific and conserved among cluster i isolates. the five carboxy-terminal amino acids were not defined due to poor coverage. availability of high-throughput snp chips for wheat [ ] and snp marker information for the majority of wheat varieties in the uk [ ] (and elsewhere) provides an unprecedented opportunity to exploit sequence data to confirm outbreaks on particular wheat varieties and look for associations between pathogen genotypes and host pedigrees. in this study, we developed an accurate system to associate samples from known wheat varieties with their corresponding snp markers. in the future, this will provide a rapid means of confirming whether previously resistant wheat varieties have indeed been broken by virulent races of the pathogen, using samples submitted directly to national pathology surveys. this would reduce delays associated with current protocols, which include pathogen propagation, subsequent virulence profiling and confirmation of a specific wheat variety using protein gels from harvested grains or similar distinctness, uniformity and stability assessments [ ] . traditionally, the surveillance of rust fungal pathogens in agroecosystems has hinged on field biology and race pathotype surveys to provide phenotypic information on pathogen diversity [ ] . however, assessments of genotypic diversity are not included routinely and when employed are restricted to just a handful of markers such as simple sequence repeats or amplified fragment length polymorphisms [ ] . our field pathogenomics approach enables the integration of high-resolution genotypic data into pathogen surveillance activities. for instance, more than million nucleotide positions were used to assess pst population diversity in this study. these highresolution genotypic data are vital to improve our understanding of the genetic substructure within a population, which provides essential information on the evolutionary forces that drive pathogen evolution within an agroecosystem. this study uncovered four genetically distinct lineages within the uk pst population, and each of these lineages had unique virulence profiles revealing a direct link between genotype and pathotype. although such a correlation has been reported for rust fungi [ , ] , our findings contrast to distantly related filamentous plant pathogens such as magnaporthe oryzae [ ] and colletotrichum lindemuthianum [ ] where a relationship between genotype and pathotype has not been detected. the time-consuming nature of traditional surveillance methods limits the number of pst isolates assessed each year. for instance, in the uk, a target number of pst-infected wheat samples are tested each year, specifically focusing on wheat varieties with a previous record of good resistance in the field. with new pst pathotypes/genotypes arising on susceptible varieties by mutation, recombination or through exotic incursions, it is unlikely that a new pathotype would be detected in a timely fashion by the current surveillance system. furthermore, an exotic isolate that displays similar phenotypic characteristics to a subset of the existing population would not be recognized as such. in this study, we uncovered a group of pst isolates (population cluster iii) that displayed identical phenotypic characteristics to a subset of the old uk population, but in fact belonged to a new emergent lineage that appears to be new to the uk. none of these isolates would have been identified as belonging to an emergent lineage based on phenotypic data alone. however, such population shifts may bear significance on disease incidence as the new population may carry important epidemiological traits other than pathogen virulence. rapid and systematic application of field pathogenomics should transform current disease surveillance systems by generating high-resolution genotypic information (additional file ) that inform disease incidence models, agronomic practices, and the selection of pst isolates for subsequent labor-intensive phenotypic characterization. the emergent pst population in the uk is now dominated by a number of newly selected, virulent clones that are adapted to an array of widely cultivated wheat varieties. by revealing genotype/pathotype-specific polymorphisms, the data we generated could prove useful in identifying candidate avirulence effectors that contribute to a pathogen's ability to evade recognition on particular host genotypes. herein, our analysis identified a small number of candidate effector genes with conserved mutations or expression profiles between members of the same population cluster that shared similar virulence profiles. ultimately, such information could be used to develop polymorphic markers to track the long-distance migration of pathotypes across wheat growing regions. we uncovered a dramatic shift in the pst population that could have serious implications for wheat production in the uk. whilst there have been widespread reports of recent changes in the pst population based on phenotypic characteristics [ ] , we report a comprehensive genetic analysis of this emergent pst population. plant-pathogenic fungi rely predominantly on recombination and mutation as the evolutionary forces that drive the emergence of new races and pathotypes [ ] . however, within a pathogen population, gene and genotype flow can shape the population substructure as propagules are exchanged between geographically separated epidemiological areas [ ] . given the clonal population structure of pst in northwestern europe, mutation and genotype flow are the primary inducers of diversity [ ] . the fact that none of the pst field isolates showed genetic similarity to the great majority of the older uk population (collected between and ; excluding pst- / ) indicates that the population is likely an exotic pst population that appears to have displaced the previous population. furthermore, the highest level of genetic diversity between the four emergent pst lineages (f st ranging from . to . ) was similar to that detected using simple sequence repeat markers and comparing pst isolates from different continents [ ] . this is indicative of distant ancestry or relatively low levels of gene flow between these emergent uk pst lineages. based on this evidence, we hypothesize that the change in pst population structure may have arisen from exotic incursions from multiple sources over recent years. future studies will focus on defining the origin(s) of this pst population. a subset of the emergent pst population we characterized displays the 'warrior' pathotype that was first detected in in the uk and is virulent on an array of previously resistant wheat varieties, including alchemy, warrior, and claire [ ] . our findings illustrate how pathogen genotype flow can trigger abrupt changes in the landscape of wheat genetic resistance to yellow rust. breeders are now at a crossroads in the uk, with few sources of yellow rust disease resistance available and the prospect of new varieties being rapidly taken off the official recommended list due to poor yellow rust resistance, as happened with torch ( year on the recommended list) and warrior ( years). with anthropogenic activities having a marked influence on the size of genetic neighborhoods [ ] , pathogen genotype flow is no longer dependent on life history traits and natural dispersal alone. the next step will be to define the boundaries of these ever-expanding genetic neighborhoods to inform surveillance strategies and breeding programs that need to take into account the full pathogen population within an isolated genetic neighborhood to breed for durable resistance. the pst isolates displayed a much higher degree of nucleotide diversity when compared with the older uk population. this reflects an increase in pst evolutionary potential in the uk pathogen population that could enhance their ability to overcome genetic resistance in the host. given that the highest levels of pst genotypic diversity have been reported in the himalayas and neighboring regions, it is possible that the emerging pst population is derived from one or more migration events from a geographic area with high sexual reproduction rates and a recombinant population structure [ ] . this is further supported by similarity in pathotypes between one lineage (cluster i) of the emergent uk population and those previously reported for exotic pst isolates [ ] . for instance, three chinese isolates that were collected in and a nepalese isolate from were shown to be virulent on the wheat variety spaldings prolific [ ] , which is a key determinant for the cluster i ('warrior') pathotype [ ] . furthermore, ali et al. [ ] previously classified two chinese isolates collected in as belonging to the northern french genotypic group (g ). future studies will focus on comparative sequence analysis between the pst isolates reported herein and global isolates of pst to determine the specific geographic origin(s) for this diverse pst population in the uk. the agronomic consequences of long-distance pathogen migration are currently unpredictable. although a pathogen population may not pose a significant threat to crop production in the country of origin, it can have devastating consequences in a new environment. for instance, in a severe stem rust epidemic in ethiopia was caused by a race similar to those detected in egypt, germany and turkey between and . however, despite the widespread devastation reported in ethiopia, other countries reported no negative effect of this race on wheat production. this episode illustrates the importance of global pathogen surveillance networks, to enable early warning systems that assess the threat of pathotypes to all crop genotypes planted within a single genetic neighborhood. field pathogenomics provides the means to generate enough markers to comprehensively genotype the pst population. high-resolution snp marker arrays would allow tracking pathogen dispersal on a global scale and clear definition of the pathogen population genetic structure. the approach reported herein uses attenuated pst-infected field samples, thereby negating the limitations associated with movement of live samples. whilst genotyping is undertaken in state-of-the-art molecular laboratories, the complementary virulence profiling can be carried out in national centers, thereby preventing any threat posed by transportation of live samples between countries. once genotypic information is generated, subsequent phenotypic characterization can focus on the most notable and representative samples ensuring the best possible use of limited national resources. in this study, we developed a robust and rapid method based on rna sequencing directly from infected host samples to gain insight into emerging pathogen populations. field pathogenomics should be applicable to surveillance of many pathogens besides wheat rust pathogens, and could contribute to addressing human, animal, and plant health issues. our approach enabled us to discover a dramatic shift in the uk pst population in essentially months after collecting the field samples. the emergent pst population has high levels of genetic diversity compared with historical uk isolates and appeared to be unrelated to the older population. this led us to conclude that the pst population was most probably derived from the recent introduction into the uk of diverse assemblage of exotic pst lineages, and that these introduced lineages may have rapidly displaced the previous pst population. such detailed knowledge of population shifts and dynamics is important for our understanding of emerging plant diseases and has consequences for the management of such diseases. a total of single lesion leaf samples of pst-infected wheat and triticale were collected directly from the field and stored in rna later solution at °c (life technologies, paisley, uk). the single lesion consisted of a to cm leaf section taken from a single infection site. total rna was extracted from of these samples using the qiagen rneasy mini kit according to the manufacturer's instructions (qiagen, manchester, uk). in addition, we extracted rna in a similar manner from infected leaves of susceptible wheat variety vuka inoculated independently with six pst isolates (pst- / , pst- / , pst- / , pst- / , pst- / and pst- / ). the quantity and quality of rna extracted were assessed using the agilent bioanalyzer (agilent technologies, edinburgh, uk). cdna libraries were prepared using the illumina truseq rna sample preparation kit (illumina, cambridge, uk). library quality was confirmed before sequencing using the agilent bioanalyzer (agilent technologies, edinburgh, uk). libraries were sequenced on the illumina gaiix at the sainsbury laboratory (for rb and rb ) or the illumina hiseq machine at the genome analysis centre, uk. adapter and barcode trimming and quality filtering were carried out using the fastx-toolkit. the -bp (gaiix) or -bp (hiseq) paired-end reads were aligned to the pst- assembly [ ] using the tophat package (version . . ) and bowtie alignment program (version . . ) with default parameters [ , ] . a similar approach was used for whole genome sequencing of pst isolates, except that gdna was extracted for each isolate from dried urediniospores using the ctab method as described by chen et al. [ ] and dna quantity was confirmed using the qubit . fluorometer. dna libraries were prepared using the illumina truseq dna sample preparation kit (illumina, cambridge, uk). sequencing of all gdna samples was carried out on an illumina hiseq machine at the genome analysis centre, uk, generating -bp paired-end reads which were aligned to the pst- assembly [ ] using bwa with default parameters [ ] . the illumina reads from all rna-seq and gdna runs were deposited in the short read archive (genbank; prjna and prjna ). first, from a set of , high-density wheat snps, , genetically mapped wheat snps were extracted [ ] . up to bp up-and down-stream of each snp site were extracted from the wheat chromosome arm survey sequence [ ] to create a reference for subsequent sequence alignments. nine pst-infected field samples were collected on wheat varieties with known varietal snp information (donal o'sullivan (university of reading) and james cockram (niab), personal communication). reads from each of these nine samples were independently aligned to the wheat genome sequences extracted above using the tophat package (version . . ) and bowtie alignment program (version . . ) with default parameters [ , ] . each of the , snp positions with ≥ × coverage was then assessed for correlation against the available sequence data for the seven wheat varieties. for each snp position, if the pst-infected field sample matched the sequence at a snp site for a particular variety (for example, variety = aa; field sample = aa) the position was scored , if the site only partially matched (for example, variety = aa; field sample = ac) then the position was scored . , and if the site had no match (for example, variety = aa; field sample = cc) then the position was given a score of . for each sample, the total score was determined and visualized for each of the seven wheat varieties. calling single nucleotide polymorphisms bam files were sorted and indexed, and snps determined using raw allele counts for each position that were obtained using pileup from samtools [ ] . heterokaryotic sites were identified as sites with allelic frequencies ranging from . to . . homokaryotic sites were those with allelic frequencies below . or above . . for both hetero-and homokaryotic sites to be reported, they had to satisfy a minimum depth of coverage of × for rna-seq data and × for genomic dna data. read frequencies were calculated for biallelic heterokaryotic snp sites and plotted using ggplot in r [ ] . homokaryotic and heterokaryotic snp sites that induced synonymous and non-synonymous substitutions were identified using snpeff, version . [ ] . all phylogenetic analysis of pst isolates was conducted using a maximum likelihood approach. first, for both genomic and rna-seq samples, nucleotide residues that differed from the pst- reference were identified and recorded if they satisfied a minimum of × or × depth of coverage, respectively. next, sites that were identical to the reference were recorded when they satisfied a minimum of × depth of coverage. finally, these sites were used to generate synthetic gene sets for each isolate and genes with a minimum of % breadth of coverage for all samples in a comparison were selected. the third codon position of these genes was then used to build maximum likelihood trees using raxml . . with replicates using the rapid bootstrap algorithm [ ] . phylogenetic trees were visualized in mega . [ ] . for the rna-seq samples, results from structure analysis were incorporated into the phylogenetic tree using itol [ ] . genetic differentiation of the pst field isolates was examined using the bayesian model-based approach implemented in the software structure, version . . [ ] via the python strauto program, version . [ ]. first, a list of , sites that introduced a synonymous change in at least one isolate was generated. then, the nucleotide at this position was extracted for all rnaseq samples. the 'admixture' model was used with three replicates of , markov chain monte carlo generations for k = to , where k is the number of populations. for each run the first , generations were discarded as burn-in before collecting data. to identify the k value the average log probability (lnp(d)) of each k value was calculated [ ] . the genetic differentiation of the field isolates was further assessed using the multivariate dapc within the adegenet package [ ] . first, , biallelic snp sites that introduced a synonymous change in at least one isolate were identified. using these data, principal component analysis was carried out to summarize genetic variation between and within potential population clusters. the optimum number of clusters was determined as the one showing the lowest bayesian information criterion. dapc analysis was then used to assign individuals to each of the population clusters. to assess the genetic diversity both within and between pst population clusters, all heterokaryotic and homokaryotic snps determined above from individual alignment of each isolate to the pst- reference were incorporated into a synthetic gene set for that isolate. the synthetic genes were combined for all pst field isolates within a population group, and genes with > % breadth of coverage for all isolates were selected. to calculate the degree of nucleotide diversity between isolates of a single population group, the degree of polymorphism between these gene sets was calculated using the dnasp software package, version . . [ ] . to determine the proportion of total genetic variance attributable to inter-population differences, the , sites that introduced a synonymous change in at least one isolate were used as input in the program genepop version . [ ] to calculate the wright's f st statistic. virulence phenotyping of pst isolates was based on the reactions of wheat cultivars possessing known resistances to pst, together with a number of cultivars possessing resistances which have not yet been fully described. tests were carried out on seedlings under controlled environment conditions [ ] , with infection types being assessed on the first seedling leaf using a to scale. infection types and were considered to represent a compatible interaction between host genotype and pathogen isolate, indicating the absence of avr alleles (that is, virulence) at the corresponding locus in the pathogen. the host resistance genes covered by the differential set were yr , yr , yr , yr , yr , yr , yr , yr , yr , yr , yr , yr , yr , yr , yr and the resistance in spaldings prolific. other discriminating differentials included the cultivars robigus, solstice, timber, warrior, ambition, and rendezvous. to distinguish the internal structure and variance within the pathology data, the scores associated with the reactions of each isolate on the differential wheat cultivars were used for principal component analysis in r [ ] . quantification of reads mapping to the pst- gene set from the pst field isolates was determined using the program htseq-count [ ] . next, the fisher's exact test, implemented as part of the edger package [ ] , was used to identify genes that were significantly differentially regulated between the four population clusters (false discovery rate < . ; p-value < . ). all isolates within each population cluster were used as replicates in the analysis to ( ) limit the influence of environmental factors on the expression profiles, as samples were collected at various sites throughout the season, and ( ) to link gene expression profiles to the virulence profiles that were unique to these genotypic groups. to identify potential effector proteins with signatures of adaptation such as mutation and variation in gene expression profiles, we focused on accessing those that were ranked the highest in our previous effector mining study [ ] . previously, we clustered protein sequences based on sequence similarity and ordered the resulting protein families based on the association of known effector features and pstspecific annotation [ ] . this resulted in overall scores for each family that reflected their likelihood of containing potential effector proteins [ ] . those within the top protein families were considered herein. primers were designed with primer version . . [ ] carrying standard fam or hex compatible tails (fam tail: ′ gaaggtgaccaagttcatgct ′; hex tail: ′ gaaggtcggagtcaacggatt ′) and with the target snp at the ′ end. oligonucleotides were ordered from sigma-aldrich (gillingham, uk) and primer mixes were as recommended by the manufacturer ( μl dh o, μl common primer ( μm), and μl each tailed primer ( μm); lgc genomics, teddington, uk). assays were carried out as described previously [ ] with the following modifications: μl reactions were used (composed of μl template ( to ng dna), . μl v × kaspar mix, and . μl primer mix)), pcr cycling was performed in an eppendorf mastercycler pro and well optically clear plates (catalogue number e , starlab, milton keynes, uk) were read on a tecan safire plate reader. data analysis was performed manually using klustercaller software (version . . . , lgc). additional file : contains supplementary tables s to s . microsoft excel workbook containing nine worksheets. table s : all pst-infected field samples collected in . table s : fungal transcripts account for a high percentage of the transcripts in pst-infected plant tissue. table s : wheat variety snps from iselect wheat snp chip (wang et al. [ ] ). table s : virulence profiles of pst isolates subjected to full genome sequencing. table s : comparison of snp sites between genomic and rna-seq datasets generated from the same pst isolate. table s : genotype data for nine pst field samples generated from kasp assays. table s : full seedling virulence tests of selected pst isolates. table s : non-synonymous snp sites where the amino acid residue was conserved among all members of a single population cluster with coverage in the region, but differed from the amino acid encoded by all members of at least one other population cluster. table s : differential expression analysis based on fisher's exact test of all pair-wise comparisons of population clusters. additional file : distribution of biallelic read counts. (a,c) read frequency at biallelic single nucleotide polymorphisms (snps) for a gdna sample known to consist of multiple mixed genotypes. the presence of several alleles with three copies and the presence of an uneven frequency distribution are indicators of more than a single genotype in the sample. (b,d) read frequency at biallelic snps for a purified gdna sample that consists of only a single pst genotype. the even frequency distribution and presence of only two alleles support the presence of a single genotype in the sample. the mode for each distribution is given in parentheses. isolation of a novel coronavirus from a man with pneumonia in saudi arabia influenza virus evolution, host adaptation, and pandemic formation hymenoscyphus pseudoalbidus, the causal agent of european ash dieback the emergence of ug races of the stem rust fungus is a threat to world wheat production the genomics of emerging pathogens transforming clinical microbiology with bacterial genome sequencing fungal molecular diagnostics: a mini review a cloud-compatible bioinformatics pipeline for ultrarapid pathogen identification from next-generation sequencing of clinical samples viral metagenomics genome evolution in filamentous plant pathogens: why bigger can be better dual rna-seq of pathogen and host the 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rust puccinia striiformis f. sp tritici isolation by distance evidence of genetic recombination in wheat yellow rust populations of a chinese oversummering area reduction in the sex ability of worldwide clonal populations of puccinia striiformis f.sp tritici differential gene and transcript expression analysis of rna-seq experiments with tophat and cufflinks ultrafast and memory-efficient alignment of short dna sequences to the human genome relationship between virulence variation and dna polymorphism in puccinia striiformis fast and accurate short read alignment with burrows-wheeler transform international wheat genome sequencing c. a chromosome-based draft sequence of the hexaploid bread wheat (triticum aestivum) genome the sequence alignment/map format and samtools ggplot : elegant graphics for data analysis a program for annotating and predicting the effects of single nucleotide polymorphisms, snpeff: snps in the genome of drosophila melanogaster strain w maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models mega : molecular evolutionary genetics analysis version . interactive tree of life (itol): an online tool for phylogenetic tree display and annotation inference of population structure using multilocus genotype data adegenet: a r package for the multivariate analysis of genetic markers dnasp v : a software for comprehensive analysis of dna polymorphism data : a complete re-implementation of the genepop software for windows and linux identification of specific resistances against puccinia striiformis (yellow rust) in winter wheat varieties. . establishment of a set of type varieties for adult plant tests r: a language and environment for statistical computing. r foundation for statistical computing a python framework to work with high-throughput sequencing data edger: a bioconductor package for differential expression analysis of digital gene expression data primer -new capabilities and interfaces submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution we would like to thank all those who submitted pst-infected wheat and triticale samples to the ukcpvs in . we thank henk-jan schoonbeek, francesca stefanato, clare domoney, tina barsby, andrew dawson, jan bettgenhaeuser and matthew moscou for logistic support; albor dobon and laura reese for assistance with wet-lab experiments; luis enrique cabrera quio for bioinformatics assistance; and mark mcmullan for useful discussions regarding population genetic analyses. this project was funded by the sustainable crop production research for international development additional file : distribution of biallelic read counts for purified uk isolates subjected to full genome sequencing. the purified uk pst isolates that were selected for genome sequencing show varying patterns of read frequencies for biallelic single nucleotide polymorphisms. the mode for each distribution is given in parentheses.additional file : all pst-infected plant samples consist of a single pst genotype. distribution of biallelic single nucleotide polymorphism read frequencies for all pst field samples (rna-seq). the mode for each distribution is given in parentheses. additional file : differential expression analysis reveals population cluster-specific expression profiles. (a) there were to genes significantly down-regulated and to genes significantly up-regulated for all isolates within a particular population cluster. differential expression analysis was undertaken using fisher's exact test from the edger package to identify genes that were significantly differentially regulated between the four population clusters (false discovery rate < . ; p-value < . ). (b) of the significantly up-or down-regulated genes, between . and . % could be annotated with potential structural or enzymatic functions based on sequence similarity searches. (c) the effector candidate pst _ was significantly down-regulated by isolates of cluster iii.additional file : snp markers developed from the field pathogenomics data could differentiate the four emergent pst lineages. of the fifteen kasp assays developed, could be used to differentiate particular lineages within the emergent pst population in the uk. each closed circle represents the genotype of a single pst field sample. blue circles, x:x; green circles, x:y; red circles, y:y; open circles, h negative control; grey circles, not determined. where shown, background color reflects grouping of field samples within particular population clusters: cluster = pink; cluster = green; cluster = blue; cluster = red. numbers reflect population clusters within each genotype group.abbreviations bp: base pair; dapc: discriminant analysis of principal components; pst: puccinia striiformis westend. f. sp. tritici eriks; snp: single nucleotide polymorphism. the authors declare they have no competing interests.authors' contributions ky, jt, sk, rb, cu and dgos conceived and designed the project; dgos designed and performed bioinformatics analysis; ky advised on population genetic analysis; ah, cml, cv-p and dgos conducted wet-lab experiments;rhr-g assisted with wheat snp analysis and designed kasp assays; cu and dgos prepared the manuscript. all authors read and approved the final manuscript. key: cord- -no mbg d authors: vandegrift, kurt j.; wale, nina; epstein, jonathan h. title: an ecological and conservation perspective on advances in the applied virology of zoonoses date: - - journal: viruses doi: . /v sha: doc_id: cord_uid: no mbg d the aim of this manuscript is to describe how modern advances in our knowledge of viruses and viral evolution can be applied to the fields of disease ecology and conservation. we review recent progress in virology and provide examples of how it is informing both empirical research in field ecology and applied conservation. we include a discussion of needed breakthroughs and ways to bridge communication gaps between the field and the lab. in an effort to foster this interdisciplinary effort, we have also included a table that lists the definitions of key terms. the importance of understanding the dynamics of zoonotic pathogens in their reservoir hosts is emphasized as a tool to both assess risk factors for spillover and to test hypotheses related to treatment and/or intervention strategies. in conclusion, we highlight the need for smart surveillance, viral discovery efforts and predictive modeling. a shift towards a predictive approach is necessary in today’s globalized society because, as the h n pandemic demonstrated, identification post-emergence is often too late to prevent global spread. integrating molecular virology and ecological techniques will allow for earlier recognition of potentially dangerous pathogens, ideally before they jump from wildlife reservoirs into human or livestock populations and cause serious public health or conservation issues. generated concern for the environment and thrust ecologists into a new political field where preserving the integrity of our global ecosystems was the priority [ ] . even so, the society for conservation biology was not established until [ ] . as a part of this transition, ecology shifted from a descriptive science to one of prediction, reflecting the hope that ecologists might mitigate changes which can have negative impacts upon the ecosystem. ecologists have branched out into the study of parasites and disease as it has become increasingly apparent that parasites are inextricably linked to the ecology of their hosts and environments, to the point where they have been a driving force in the evolution of sexual reproduction and in the shaping of biodiversity [ , ] . over the past years, disease ecologists have developed the study of parasites and pathogens in the wild. this knowledge has been synthesized into mathematical models which describe the dynamic properties of ecosystems and predict how parasites and pathogens flow through them. [ , ] . these models are becoming more commonly integrated into epidemiological studies that seek to predict outbreaks or periods of time when cross-species spillover risk is highest. parallel to this progress, the field of virology, particularly the subfields of molecular virology and viral evolution, have also been burgeoning, largely due to advances in technology that have made molecular assays and genetic sequencing more accessible to a greater number of scientists. the development of high-throughput sequencing has greatly increased our ability to efficiently detect known viruses as well as to discover new types of viruses, thereby improving our understanding of viral diversity, pathology and evolution. this increased capacity has spawned the development of new fields of study. for example, phylodynamics allows researchers to determine the origin of circulating viruses in space and time. mutations among viral strains can be used to investigate interactions among host species as well as long-range host movement via corridors and flyways. phylodynamic analyses can also inform livestock management practices, as was the case with foot and mouth disease in the united kingdom [ ] . conducting viral surveillance in animal reservoirs and invertebrate vectors can help explain circulation within host species; observed patterns of zoonotic transmission; and even allow for the prediction of periods of increased risk of zoonotic transmission (e.g., rift valley fever and rainfall [ ] ; west nile virus (wnv) and american robin (turdus turdus) migration [ ] ; as well as hantavirus in mice [ , ] ). understanding viral ecology in wildlife reservoirs and identifying high-risk human-wildlife interfaces is especially critical in the context of ever increasing globalization, whereby transportation networks facilitate rapid spread of pathogens well beyond bounds where traditional epidemiological methods can be effective [ ] [ ] [ ] . the influenza a (h n ) pandemic spread from the presumptive point of emergence in la gloria mexico to new zealand in just under a month [ ] while sars radiated from guangdong, china to different countries within several months [ ] . the negative impacts of emerging infectious diseases are not limited to humans. indeed, wildlife conservationists have documented several mass mortality events in other animal species. western lowland gorillas (gorilla gorilla gorilla) have been decimated by ebola virus [ ] and an especially virulent calicivirus, rabbit hemorrhagic disease virus, spread through both domestic and wild rabbit populations, resulting in tens of millions of deaths [ ] . in some instances the viruses have attenuated, while in others the animal populations have been brought to the brink of extinction. importantly, the risk from disease to humans and animals should not be separated. the global transportation network facilitated the introduction of infected vectors (e.g., mosquitoes) into new york and wnv caused both avian and human mortality, and this virus has subsequently spread across the united states [ ] . table . definitions of key terms used in the text. the formation of a hybrid population through the mixing of two ancestral, or long-separated, populations. a method for estimating historical population dynamics from a sample of sequences without assuming a predefined demographic model. coalescent theory a mathematical framework which describes the distribution of gene trees in populations. it provides mathematical methods for connecting demographic or ecological models with a phylogenetic tree. demography is the statistical study of populations. in the field of ecology, demography encompasses the study of the size, structure and distribution of populations, and spatial and/or temporal changes in them in response to birth, migration, aging and death. however, here we use a more rigid definition of demography-as the pattern and rate of population growth. the number of breeding individuals in an idealized population that would show the same amount of dispersion of allele frequencies under random genetic drift, or the same amount of inbreeding, as the natural population under consideration. the analogue of ne for viruses, the ‗effective number of infections' is related to the number of infected host individuals and to the number of new transmission events [ ] . a discipline which uses next-generation sequencing technologies to characterize the entirety of genomic material found in environmental samples. the molecular clock is derived from the hypothesis that sequence evolution, while random, occurs at stable rate such that the time since the divergence of two or more sequences can be estimated. recent ‗relaxed molecular clock' analysis can account for variation in the rate of sequence evolution through time or between lineages. the relations among a set of sequences showing which shares a most recent common ancestor with other sequences. the study of the principles and processes governing the geographical distribution of genealogical lineages. in the field of population genetics, population structure is defined as the absence of random mating within a population. this is the definition used here. in ecology, population structure is defined by several key parameters including number of individuals in a population, age distribution of individuals, probabilities of survival (or mortality), and rates of fecundity. a process that occurs in segmented viruses by which one or more segments ‗swap' to create a new viral genome. this drives the process of antigenic shift in influenza a viruses. the process by which new genotypes are created by the combination of distinct lineages. in sexual organisms it occurs during meiotic division, by the exchange of dna between different chromosomes or ‗crossing-over'. viral recombination occurs during viral replication and is an important factor in viral evolution (for more details see worobey and holmes, [ ] ). mutation of a virus such that it changes ‗back' to its wild-type state. the timing of an organism's schedule of reproduction and death. species with long life histories, also known as ‗k' strategists, tend to have low reproductive rates, stable populations, long generation times and long lifespans. where the parasite population is not randomly distributed among hosts, such that the variance is greater than the mean. the macroparasites in a host population are often best described by the negative binomial distribution such that a minority of hosts possess the majority of the parasites. r (basic reproduction number) in the case of viruses and other microparasites, r is the average number of secondary infections which an infection produces. as such it is a measure of parasite fitness. a host species that can independently maintain a disease and act as a source of infection to other host species. infection in reservoirs is usually more persistent and less harmful than that of other hosts. zoonotic disease a disease transmissible from animals to humans or vice versa. globalization, host ecology, host-virus dynamics, climate change, and anthropogenic landscape changes all contribute to the complexity of zoonotic viral emergence and disease, and create significant conservation and public health challenges. comprehensive and collaborative scientific approaches that transcend disciplinary boundaries are necessary to address these challenges. it is the goal of this paper to review new methods for understanding viral dynamics and illustrate how and when these techniques can be used by not only public health officials, but also disease ecologists and conservation biologists. the phylodynamic paradigm, established in [ ] , exemplifies the power of a multidisciplinary approach. it unites the ecological and evolutionary study of viruses and builds upon advances in sequencing technologies and coalescent theory, by which gene genealogies are reconstructed backward in time [ ] . the analysis of phylogenetic trees enables researchers to address many of the primary questions posed by disease ecologists (figure ). in some cases this approach can provide an estimate of a virus's basic reproductive number (r ), which is a measure of parasite fitness [ ] . phylodynamics has far-reaching applications for the control of viruses in both human and animal populations, in addition to being vital to our understanding of the interconnectedness between them. phylodynamic studies can be used to identify reservoir species as well as defining the spatial and temporal origin of emerging infectious diseases [ ] . they can also help to elucidate how these viruses spread following their emergence [ ] . firstly, chains of viral transmission can be extrapolated from the branching topology of phylogenetic trees. one example of the utility of this approach is with rabies virus. rabies causes thousands of human deaths a year in africa and has been implicated in the decline and local extinction of several populations of african wild dog (lycaon pictus) [ , ] . lembo et al. analyzed sequences of rabies virus from the serengeti, revealing that domestic dogs were the reservoir of the virus and that they had transmitted it to other resident carnivore populations on repeated occasions [ ] . this work has applicability in that it can be used to design efficient and effective vaccination strategies, both to alleviate current distress and prevent future outbreaks [ ] . secondly, by mapping the geographical origin of each sequence onto the nodes of phylogenetic trees, the geographical origin of a virus might be identified. wallace et al. ( ) [ ] used this phylogeographic approach to identify guangdong province, china as the most parsimonious origin of highly pathogenic h n strain of avian influenza and to delineate the most likely pathways of viral spread [ ] . however, a recent bayesian analysis of this data did not support the conclusion that h n had dispersed from guangdong to indonesia [ ] . instead, the bayesian analysis suggested it had spread to indonesia from guangxi or hunan in china. this example demonstrates that different statistical techniques may yield different conclusions. as yet, neither the bayesian nor the frequentist method is universally considered to be superior and there is much room for improvement as statistical phylogeography develops as a field. phylogeographic tools have also been applied by walsh et al. ( ) [ ] to locate the putative origin of the zaire strain of ebola virus. in an attempt to resolve the controversy over the time of emergence and spreading trajectory of ebola in the congo basin, they then used spatial data and two different tests for the impact of selection on the virus genome [ ] . where a virus is expanding in range, as the zaire strain of ebola virus appears to be, using a ‗landscape genetics' approach may help identify geographical barriers to viral spread and help identify vulnerable human or wildlife populations lying in the path of infection [ , ] . these phylogenies may reflect transmission chains, however sampling must be sufficient for them to do so, while recombination may obscure ‗true' relationships between viral sequences. (b) simple molecular clock theory, predicated on the neutral theory of molecular evolution [ ] assumes that mutation occurs at a constant rate over time, thus the time that has elapsed since a pair of virus strains diverged from a common ancestor may be quantified. methods that account for differences in the evolutionary rates of different strains, and for variation in these rates through time, have been recently developed [ ] . here variants represented by thick lines evolve much faster than those represented by thin lines. (c) using a phylogeographic approach, the location at which a sequence was sampled may be mapped onto the viral phylogeny and the likely spreading trajectory of the virus inferred. while parsimony approaches have been popular, powerful bayesian methods that account for uncertainty of dispersal process and historical phylogeny have been developed to reconstruct viral dispersal events [ ] . crosses on the phylogeny represent such viral dispersal events, in this example. (d) coalescent theory provides the basis for many phylodynamic approaches. here, circles on the same row represent temporally simultaneous infections. working back from sampled infections (red circles), lineages can be traced back to the most recent common ancestor (black circle) via hypothetical, unsampled ancestors (grey circles). the time it takes for sampled lineages to coalesce is dependent on a variety of variables (i.e., viral effective population size, population structure, selection, stochastic infection die-out and recombination). a variety of methods are available to test for selection and recombination. phylodynamic analyses are not without limitations. dense and representative sampling at a scale equivalent to epidemiological surveys is required to fulfill the potential of phylodynamics for understanding epidemics of rapidly-evolving viruses [ ] . the construction of phylogenetic trees from these viral sequences may be complicated by recombination and, in the case of segmented viruses, reassortment of viral genomes [ ] . as a result of these processes, the genes on a single viral sequence may have very different origins (see the discussion of the different origins of the hemagglutinin and neuraminidase segments of h n avian influenza in lemey et al. [ ] ). therefore, concatenated analysis of multiple genes may be confounded. the ability to construct phylogenies is further limited by the total viral genetic information available. genbank is a vast public database that contains records of genetic sequences; however, its usefulness is dependent upon the willingness and/or ability of individuals and organizations to submit viral sequences. governments and industrial institutions may be reluctant to report sequences of economically important viruses (i.e., avian influenza) due to the potential negative economic impacts that may ensue. although phylodynamics is currently encumbered by the aforementioned factors, there is hope for progress. advancements in coalescent theory will help us to deal with the phylogeny construction problems caused by recombination and reassortment. they will also facilitate better utilization of genomic and spatial data, provided these advancements are also accompanied by a simultaneous increase in computing power, which is also currently limiting. the utility of phylodynamics is not limited to questions of interest to virologists and disease ecologists. this approach may also inform investigations of host population biology and, in so doing, aid in the development of conservation policy. host molecular markers (e.g., microsatellites, mitochondrial dna) are used by conservation biologists and ecologists to infer population structure, historical demography and other critical features of wildlife populations [ ] and have proved particularly powerful when analyzed in combination (i.e., [ , ] ). recently, it has been demonstrated that the pathogens of host populations might also be useful to this end. research using helminths and bacteria has revealed patterns of ancient human migration and dispersal [ , ] identified ancient refuges of rodent and bird taxa [ , ] and shown that there was past contact between contemporary non-sympatric bat species [ ] . however, there have been few attempts to utilize viruses to this end (save [ , ] ). it is surprising that viruses have not been used more for the inference of host population biology since some of their characteristics make them ideal for doing so. most viruses have large population sizes and short generation times, and many replicate using a highly error-prone rna-dependent rna polymerase, causing them to accumulate many more mutations (nucleotide changes) per unit time than the host genomes [ , ] . consequently, viruses may provide information about host demographics on a shorter timescale than molecular markers of the host. one of the signature tools of phylodynamics, the bayesian skyline plot, might also be utilized to infer changes in historical population size of the host. these plots incorporate the use of a molecular clock and coalescent theory to infer historical changes in virus population sizes without assuming a predefined demographic model [ ] . it is important, however, that the timescale over which the evolutionary dynamics of the virus population can be reliably reconstructed is appropriate for the parameters of interest in the host population. unfortunately, the very characteristics that make viruses useful for estimating host population structure and demography may also impede the analyses. multiple substitutions can occur quickly in the viral genome and this will obscure the host population's actual evolutionary history. meanwhile, variations in the transmission mechanisms of viruses (vertical vs. horizontal) can alter the ability to accurately infer a virus' relationship to a host population. cross-species transmission is also problematic in that it can cause pathogen phylogenies to inaccurately reflect the history of their hosts [ ] . therefore, before the genetic information contained within a virus population can be used to infer the population structure and demography of the host, it is critical to test for congruence in the evolutionary history of the host and virus populations. this is accomplished by statistically comparing the respective phylogenies within the relevant timescale. viruses with high host specificity have a greater likelihood of exhibiting such congruence. feline immunodeficiency virus (fiv) is known for high host specificity and is, thus far, the only virus to have been used to elucidate changes in host population structure and size. from a phylogenetic analysis of fivpco, the fiv type specific to the cougar (puma concolor), biek, drummond, and poss ( ) [ ] inferred that the north american population of cougars became subdivided during the last century but subsequently expanded in both size and range. subsequently, antunes et al. ( ) [ ] used the distribution of fiv ple subtypes in the serengeti to infer that recent admixture has occurred between the region's lion (panthera leo) populations. these recent changes in felid population size and structure could not have been inferred from host genetic data. there is great potential for the further use of this technique by conservation biologists and ecologists, and for it to complement existing methods which utilize host genetic data. host genetic markers are used to define management units for conservation purposes [ ] . many ‗flagship' endangered species have long life histories [ ] , a feature that correlates with both extinction risk in certain regions [ ] and difficulty in reconstructing recent demographic history from molecular markers. because of the latter, the use of viral genetics to define management units may be an important avenue of exploration. in addition to aiding the definition of management units, viral data could be used to analyze the consequences of management activities and other environmental changes on target species. where viral genetic diversity exists in a spatially heterogeneous distribution, viral movement patterns could be used to study the migratory behavior of animals (as macroparasites have been [ , ] ). as such, researchers could monitor the use of wildlife corridors and the efficacy of control measures aimed at limiting the range of a host species [ , ] . where viruses can be readily amplified from non-invasively collected samples (see [ ] ), the above objectives could be achieved in a cost effective manner with minimal disturbance of the study species. viruses with specific transmission routes may also serve as proxies for behaviors related to transmission (i.e., sexually transmitted diseases). similarly, where cross-species transmission occurs, viruses might be indicative of types of sustained, direct contact between different, sympatric taxa which facilitate such transmission, for example predator-prey interactions [ ] . at the broader ecosystem level, inferences about long-term evolutionary processes might also be made by examining the phylogeographic structure of numerous host and virus populations of a region (see [ ] ). a major hurdle for both virologists and ecologists is defining the biodiversity of life. at present, scientists do not know the actual number of mammal species, much less the diversity of viruses they harbor [ ] . indeed, the diversity of viruses known to infect the house mouse (mus musculus), a staple in biomedical research, is not yet completely known. recent advances in genetic sequencing, including high-throughput sequencing and other -next-generation sequencing‖ techniques, as well as masstag pcr and microarray multiplex assays [ , ] have made the study of microbial diversity feasible [ ] . these technologies have facilitated a movement from classical virology, where the focus was on disease etiology, toward a broader discipline that considers the rest of the viral diversity or -the virosphere‖. metagenomic studies have used next-generation sequencing to study biodiversity in substrates such as ocean water and soil [ , ] . metagenomics has also been used to screen human and animal clinical samples in order to determine etiologic agents of disease or to describe the microbial flora normally present in a vertebrate host-in many cases the result has been the discovery both of novel pathogens and novel associations between clinical disease and agent [ ] [ ] [ ] [ ] . as technology becomes more affordable, and thus accessible, there will be increasing opportunities to ask large-scale questions such as: how does the virosphere vary across space and time? how does it vary across species? can we use this to define risk of cross-species transmission or to inform conservation efforts? and how might co-infections with these undiscovered viruses influence the dynamics of the more well known viruses? the paucity of information about viral diversity within a host poses problems for research progress. it is difficult to understand viral pathogenesis and transmission without completely understanding the dynamics of co-infections. indeed, it is currently difficult to ascribe a host's symptoms to an individual virus with any certainty because a virus' actions, and even its ability to infect the host, could be a function of another (possibly undetected) co-habitant of the host. evidence of interactions between co-infecting species has been clearly demonstrated [ , ] and it will be critically important to elucidate the interactions that occur between multiple pathogens as well as the combined effects they may have on a host's immune system. broadening our understanding of the diversity of pathogens that exist in human and animal hosts through wildlife and domestic animal surveillance will significantly improve our ability to recognize novel zoonotic agents in the context of a disease outbreak. phylogenetic information obtained from comparative sequence analyses can improve our understanding of the impact of sequence mutation on virulence, as well as inform decisions about vaccine development. a final noteworthy benefit of viral discovery efforts is that these techniques should be important for identifying candidates for future vaccines as a virus's most worthy competitor is often another virus. from a health perspective, vaccination is arguably the most important technology that has arisen from the study of viruses. vaccination offers a direct means of intervening in a host-pathogen system and it has become routine in many parts of the world. efforts to this end have resulted in the eradication and/or control of smallpox, polio, mumps, measles, rubella and most recently, rinderpest. vaccines take several forms including live-attenuated viruses; inactivated whole viruses; inactivated toxins and viral protein subunits, and these are often delivered in combination. while live-attenuated vaccines have been predominant, a new generation of techniques including gene delivery and nano-technologies are being used to develop highly-efficacious and safer vaccines, that have less risk of reversion [ ] . new types of administration methods are also being developed with oral, aerosolized and nasal vaccines currently on the market. these less invasive administration techniques decrease labor costs associated with administration and offer increased capacity for mass-dispersal of vaccines to both humans and free-ranging wildlife [ ] . vaccination campaigns aimed at both protecting threatened species and decreasing public health risks via animal vaccination have taken place. swiss health officials were pioneers in this field, using oral vaccines to control rabies in wild red foxes (vulpes vulpes) [ , ] . these vaccines were inserted into chicken heads which were distributed in the wild beginning in [ ] . as can be observed from the supplemental movie (video s ), their initial barrier approach evolved into a large-scale treatment of infected areas and resulted in rabies being successfully pushed back to and then eliminated from the swiss alps [ , ] . following the success of these trials, campaigns were conducted in western europe [ ] and canada [ ] with similar results, though the situation in the united states has proven more challenging. other successful vaccination examples include canine distemper virus in black-footed ferrets (mustela nigripes; [ ] ) and ethiopian wolves (canis simensis; [ ] ), as well as rabies in florida panthers (felis concolor coryi; [ ] ) and african wild dogs [ , ] . a caveat to this success is that there is growing evidence that vaccination against a specific strain of pathogen can result in inadvertent selection for related co-infecting strains. thus vaccination can influence the dynamics of a pathogen [ ] . the possibility of inadvertent viral strain selection highlights the importance of understanding the long-term evolutionary and ecological consequences of vaccination. indeed, where threatened or endangered animals are concerned, mishaps may prove disastrous. attenuated canine distemper vaccines did not provide immunity to critically endangered black-footed ferrets, while the use of a live canine distemper virus vaccine resulted in clinical distemper arising in one of the few remaining populations [ ] . ideally, long-term clinical trials with suitable animal models might avert these problems. these trials should also be used to provide an a priori understanding of how vaccination might shape future evolutionary processes. in contrast to the ferret experience, efforts with the endangered ethiopian wolf serve as an example of a successful vaccination program. wolf populations were suffering severe mortality due to rabies and distemper acquired from the wild dogs that shared their home range [ ] . on the basis of a spatially explicit individual-based model, which indicated rabies could be controlled in dogs given just over % coverage [ ] , knobel et al. executed an intensive vaccination plan [ ] . both the extent and duration of outbreaks in the treated areas were limited and, although monitoring and continued vaccination are required, the situation appeared to be under control in [ ] . wildlife vaccination campaigns are also being investigated as tools to limit public health risks. tsao et al. vaccinated mice in an effort to break the cycle of lyme disease and reduce the risk of emergence in human populations, in which it causes tens of thousands of deaths per year in the us [ , ] . in the same vein, griffing et al. [ ] have tested the efficacy of vaccinating american robins to interrupt the wnv transmission cycle. this species can absorb up to % of the potentially infective mosquito bites in early spring and is thus a key host in the wnv system [ ] . targeted vaccination of this single species could potentially result in herd immunity and reduce the risk of human infection as well as decreasing wildlife mortality. these works exemplify how ecological knowledge can be used to identify and exploit some of the heterogeneities which so often dominate the dynamics of pathogens. while the lasting efficacy of wildlife vaccination efforts has yet to be demonstrated with either endangered species or in breaking the transmission cycle of human pathogens, an increasing number of researchers are drawing attention to systems where it seems feasible [ , ] ; demonstrating that intricate knowledge of host and virus ecology can greatly reduce the amount of vaccine coverage that is necessary to control these viruses. the problems entailed by the sheer number of viruses, viral resistance, the explosive potential for spread, and the economic burden, make it clear that currently available vaccination methods do not provide a sustainable solution for either human or animal disease. the unambiguous indication is that researchers need to work towards the goal of developing a predictive framework where risk can be defined for different scenarios and not only to rank pathogens, and species, but also, places and times of year that can be identified as more or less precarious for global health. pending questions include: which geographic areas will experience more disease and conservation problems? which areas pose the highest risk for pandemic spread of pathogens? what characteristics of hosts and viruses make them more or less likely to be involved in cross-species transmission events? and what are the relative roles of genetic relatedness and contact rate for transmission? some modeling work and reviews of historic data have been informative [ , ] , but novel uses of phylogenies of both viruses and hosts (as discussed above) provide promise for progress to this end, especially when coupled with high quality surveillance data. once we have this information, scientists will be able to design -smart surveillance‖ strategies whereby valuable vaccine resources can be efficiently targeted and efficiently distributed. ecological studies can effectively inform conservation as well as public health policy. gaining knowledge of reservoir host ecology can be critical for the development of eradication strategies. most viral disease systems are dominated by heterogeneities and identifying and understanding these can be crucially important when trying to interrupt the chain of events that leads to persistence. ecological studies of wnv have shown how forest fragmentation and decreased biodiversity can alter transmission among avian hosts as well as to humans [ ] . likewise, researchers have used satellite imagery to identify habitat characteristics that accurately predict the prevalence of sin nombre virus [ , ] , a hantavirus that uses the deer mouse (peromyscus maniculatus) as a reservoir host and it occasionally infects and kills humans [ ] . these studies epitomize the type of effort scientists will need to successfully fight viral pathogens in the future. however, piecing together emerging disease and conservation problems ex posto facto is only of limited value. increased pathogen surveillance and ecosystem process monitoring may provide the insight necessary to mitigate problems before they become serious human health or conservation concerns. this is especially the case for zoonotic viral pathogens where the reservoir hosts are known and a targeted approach is feasible. rodents rank as the number one reservoir of emerging and re-emerging zoonotic viruses [ ] . conveniently, these small mammals also present a manageable system for studying disease dynamics [ ] [ ] [ ] . individuals can be marked and sampled individually through time. their locations as well as their contacts with other individuals can be measured. as such, wild populations of rodents can be valuable as model disease systems to address relevant questions like: are there key hosts for transmission? how does prevalence vary seasonally or over time? what is the contact rate between the reservoir and humans? how do these pathogens flow through populations? the answers are of critical importance because they provide an indication of when and where there is increased risk of a zoonotic event whereby a human becomes infected, or when a species becomes at genuine risk of extinction. by monitoring and manipulating wild populations, one might also be able to identify factors that may increase a pathogens chance of emerging. for instance, what characteristics of hosts and viruses make them more or less likely to be involved in cross-species transmission? and what are the relative roles of genetic relatedness and contact rate for transmission? long-term monitoring and surveillance in reservoirs will also enlighten us to the kind of aggregations and other heterogeneities that exist through time and that and can be exploited with efficient vaccination campaigns. we are experiencing a global increase in the rate of emerging viral zoonoses, which are primarily driven by anthropogenic activities such as land-use change, agricultural intensification, and driven by global travel and trade [ ] . in order to adequately understand, predict and ultimately interrupt the processes by which zoonoses cross the species barrier from their natural reservoirs to humans, and then become established as human pathogens, comprehensive scientific studies that use the tools of ecology, virology, microbiology, and epidemiology are needed [ ] . the study of disease ecology has become an established discipline with advances in both the formulation of new theory as well as the integration of molecular virological techniques that provide important information about epidemiology, ecology and viral evolution, all of which has been applied to both health and conservation [ ] [ ] [ ] . because ecological systems are rife with heterogeneities and often have non-intuitive processes underlying their dynamics, it is critically important for scientists to use a comprehensive approach to understanding the population processes of an ecosystem before successful intervention strategies can be developed or implemented. admittedly this is a daunting task and it is often the case that scientists need to operate with less than complete information. where this is the case, a modeling approach is necessary to identify key processes that allow successful interventions. technological advances in molecular virology and genetics, as well as the expanded use of mathematical models in epidemiology and disease ecology have dramatically changed our ability to manage both conservation and health. 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endangered species an ecological approach to preventing human infection: vaccinating wild mouse reservoirs intervenes in the lyme disease cycle mosquito landing rates on nesting american robins (turdus migratorius). vector borne zoonotic dis vaccination of wildlife to control zoonotic disease: west nile virus as a case study transmission dynamics and prospects for the elimination of canine rabies global trends in emerging infectious diseases ability to replicate in the cytoplasm predicts zoonotic transmission of livestock viruses land use and west nile virus seroprevalence in wild mammals satellite imagery characterizes local animal reservoir populations of sin nombre virus in the southwestern united states ecology of hantaviruses and their hosts in north america. vector borne zoonotic dis chain reactions linking acorns to gypsy moth outbreaks and lyme disease risk could parasites destabilize mouse populations? the potential role of pterygodermatites peromysci in the population dynamics of free-living mice, peromyscus leucopus predicting the emergence of human hantavirus disease using a combination of viral dynamics and rodent demographic patterns anthropogenic environmental change and the emergence of infectious diseases in wildlife collaborative research approaches to the role of wildlife in zoonotic disease emergence ecology of infectious diseases in natural populations the ecology of wildlife diseases conservation medicine and a new agenda for emerging diseases this work was supported in part by nih/nsf -ecology of infectious diseases‖ awards from the john e. fogarty international center (grant r -tw - s ) and an nih award (k ai ) from the national institute of allergy and infectious diseases. we thank c. j. wale, b. wale and h. ewing for their help in proofing the manuscript. key: cord- -uwi ezd authors: korevaar, hannah; metcalf, c. jessica; grenfell, bryan t. title: structure, space and size: competing drivers of variation in urban and rural measles transmission date: - - journal: j r soc interface doi: . /rsif. . sha: doc_id: cord_uid: uwi ezd a key concern in public health is whether disparities exist between urban and rural areas. one dimension of potential variation is the transmission of infectious diseases. in addition to potential differences between urban and rural local dynamics, the question of whether urban and rural areas participate equally in national dynamics remains unanswered. specifically, urban and rural areas may diverge in local transmission as well as spatial connectivity, and thus risk for receiving imported cases. finally, the potential confounding relationship of spatial proximity with size and urban/rural district type has not been addressed by previous research. it is rare to have sufficient data to explore these questions thoroughly. we use exhaustive weekly case reports of measles in urban and rural districts of the uk ( – ) to compare both local disease dynamics as well as regional transmission. we employ the time-series susceptible–infected–recovered model to estimate disease transmission, epidemic severity, seasonality and import dependence. congruent with past results, we observe a clear dependence on population size for the majority of these measures. we use a matched-pair strategy to compare proximate urban and rural districts and control for possible spatial confounders. this analytical strategy reveals a modest difference between urban and rural areas. rural areas tend to be characterized by more frequent, smaller outbreaks compared to urban counterparts. the magnitude of the difference is slight and the results primarily reinforce the importance of population size, both in terms of local and regional transmission. in sum, urban and rural areas demonstrate remarkable epidemiological similarity in this recent uk context. though widespread vaccination has greatly reduced global transmission of measles since the mid- s, it continues to be a major cause of death among children in sub-saharan africa [ ] . additionally, re-emergence of measles in many parts of the world due in part to vaccine hesitancy emphasizes the importance of continued attention to measles [ , ] . more broadly, in an increasingly urbanized world, understanding the impacts of urbanization and population density on transmission of highly contagious infections such as measles are increasingly urgent [ ] . a simple epidemic clockwork and detailed and reliable notification systems across urban and rural settings, makes measles one of the best documented spatio-temporal consumer-resource model systems generally, and a particularly apt candidate for examining disease interactions across diverse population densities [ ] [ ] [ ] [ ] . urban and rural disparities in health have been studied in a variety of contexts. in the usa, the urban-rural gap in life expectancy has widened over the last four decades. this is due in large part to mortality of individuals under the age of and correlates with accidental injury and reduced access to highquality medical care [ , ] . the incidence of dengue is known to be higher in urban areas [ , ] , whereas the burden of malaria is higher in rural areas [ ] . in rural areas, increased likelihood of concurrent sexual contacts increases the risk for hiv and other stis [ ] . seasonal migration between urban and rural areas also impacts transmission of infection [ ] . while these papers have investigated differences in urban and rural health outcomes, disease burden, and migration few have explored the urban/rural hierarchy in transmission across a metapopulation or attempted to quantify differences in transmission due to urban/rural environment. this study allows an investigation into differences within urban and rural areas in addition to differences between urban and rural areas as part of a larger, connected population. ferrari et al. show that population size is the most consistent driver of the magnitude of epidemic seasonality in measles epidemics in niger across urban and rural districts [ ] . rainfall and agriculturally induced variation in contact rates also impact the amplitude of seasonality. the authors find reduced seasonal forcing in sparsely populated areas with the highest seasonal amplitudes present in large and/or densely populated areas. a comparable investigation of urban and rural districts in a context where school calendar forcing is the dominant mechanism has not been done. the consistency of seasonality in england and wales (hereafter e&w) as a result of the school calendar provides a unique opportunity to compare transmission rates and epidemic dynamics while isolating urban/rural status from other potentially confounding factors such as climate, variation in seasonal contact rates, population size and proximity to epidemic pacemakers. additionally, the granularity of the data as a result of the number of districts ( ) and the duration of notification data before vaccination ( years) is unparalleled. measles is a paradigmatic infection for investigating nonlinear dynamics of disease transmission [ ] [ ] [ ] . infection with strongly immunizing pathogens such as measles results in either death of the host, or more often, recovery and lifetime protection. compartmental models, such as the susceptibleinfected-recovered (sir) model are useful as simple models of disease dynamics but can be difficult to adapt to data. the sir model assumes a well-mixed population, and in the most basic form balances demographic processes (e.g. births, deaths and immigration) with properties such as contact rate, β, and infectious period particular to a given pathogen. in general, the transmission coefficient, β, varies seasonally, in the case of measles, this seasonality is largely driven by the school calendar. while the simplicity of the sir model is beneficial for interpretability and cross-setting comparisons of transmission, calibrating the seasonality-forced sir model against data can be statistically challenging [ , ] . the main challenges of fitting the sir model to data result from two sources: only one state variable is observed (the number of cases) and rates of under-reporting are not known. a computationally efficient option for addressing both these challenges is the time-series sir (tsir) model. the tsir model relies on two main assumptions: first, the infectious period is fixed at the sampling interval of the data (e.g. biweekly for measles) and that over a long enough time (e.g. - years), the sum of births and cases should be approximately equal due to the high infectivity of pathogens such as measles and other childhood infections. both of these assumptions have been thoroughly tested and found to be largely appropriate for this pre-vaccine era data [ ] . fixing the infectious period to be equal to the sampling period means we assume an individual that is infected at the n time step will be recovered by n + . highly transmissible childhood infections, such as measles, can spread quickly through a community until the susceptible population is depleted, to the point that it can lead to local extinction. thus measles requires a steady stream of new susceptible hosts (mainly from births) to remain endemic. for this reason, large populations, typically above , are required for sustained transmission-this threshold is called the critical community size (ccs). for communities below the ccs, future outbreaks are dependent on imported infections from other locations [ ] . in these small populations, the susceptible proportion will increase until the pathogen is reintroduced through spatial transmission from a neighbouring community. these metapopulation dynamics, the reintroduction of infections via spatial contacts, are a characteristic component of measles transmission in e&w during pre-vaccination years [ , , ] . endemic areas such as london would act as epidemic pacemakers, replenishing infections for communities below the ccs threshold. echos of london's strong biennial epidemic pattern radiate across the surrounding region, creating biennial epidemics in locations that would otherwise be too small to experience such regular outbreaks [ ] . quantifying rates of spatial transmission is a crucial challenge for epidemiologists as the spread and persistence of pathogens depends on this connectivity between large and small places [ , [ ] [ ] [ ] . population gravity and spatial hazard models have been used to estimate movement of individuals across locations [ ] [ ] [ ] [ ] . population gravity models assume that movement between locations can be approximated by the product of the population size normalized by a transformation of the distance between them. under these assumptions, we expect movement between large places to be high, movement between small places to be low, and for contact between communities to decline with distance. these models have been able to successfully capture population movement in the context of disease transmission in some cases [ ] . though gravity models have provided useful insights into the spatial interactions of many human and non-human disease systems, in the absence of independent covariates describing human movement, the simultaneous inference of epidemic trajectories and spatial coupling is difficult. information on the movement of school age children is notably sparse. as school age children are the population of interest in this case, we opt to avoid weighting by population and allow the reconstructed susceptible population to guide our probabilistic model. furthermore, research has shown that for this dataset in particular, gravity models have not adequately captured the dynamics of large cities with off-year peaks or coastal cities [ , ] . finally, gravity models do not assume different contact rates by urban or rural location type and we may expect contact between urban locations to be higher regardless of population size. for these reasons, we use a spatial hazard model to calculate the spatial coupling associated with each location. resulting estimates are informed by the measles case data (using susceptible and royalsocietypublishing.org/journal/rsif j. r. soc. interface : infectious dynamics to determine infection probabilities) and assume no predetermined functional forms, so that estimates of coupling for each location are not constrained by location size or distance [ ] . spatial coupling provides an estimate of how much a district's epidemic dynamics are influenced by the influx of new cases from other locations. previous hazard-based coupling estimates suggests that transmission across locations is strongly correlated with population size [ ] . bjornstad et al. use a spatial hazard model to estimate spatial coupling for all urban areas in the dataset. the authors show larger places exhibit larger coefficients of spatial coupling than smaller, more isolated places, and thus more coordination with national epidemics. additionally, the authors use residuals from linear regression of spatial coupling on population size to show that locations near large endemic locations (such as london, manchester and birmingham) have higher than expected estimated rates of coupling than other locations of comparable size. similarly, locations very far from these population centres produce lower than expected coupling rates. this highlights the importance of both size and space in cross-location measles transmission. by contrast, research on data from e&w suggests transmission within locations does not scale with location size. bjornstad et al. [ ] use a subset of sixty cities in e&w to show that while transmission rates demonstrate some variability across locations, they do not vary uniformly with population size. the authors select locations of various sizes and calculate the basic reproduction number based on the epidemic data. the basic reproduction number (r ) is a parameter commonly used to quantify the contagious power of disease, it is defined as the number of secondary infections resulting from a single infected individual if everyone else in the population is susceptible. population level estimates of r for measles are commonly between and [ ] . though the estimate can vary, bjornstad et al. posit that it does not vary systematically by population size. this is likely because schools act as transmission hotspots and the importance of these focus points outweighs any impact of population size. furthermore, measles has a particularly high transmission rate: infected individuals are contagious for up to days before they show symptoms and the measles virus is airborne and can survive up to hours in airspace. these factors make the disease highly contagious. for this reason, once an infection is introduced to a susceptible population it will spread rapidly. as these infections will largely spread in schools, any differences due to population density are believed to be marginal, particularly in the case of e&w [ ] . estimates of transmission allow us to measure withincommunity epidemic dynamics. spatial coupling allows us to estimate how these locations differ in their connection to metapopulation dynamics. we can, therefore, measure potential differences between urban and rural locations locally as well as contextually. however, we know spatial proximity plays a key role, both in terms of the local population dynamics as well as the number of imports a location can expect to receive. we also know urban and rural areas are not distributed randomly in space (both rural and small population locations are more likely to be farther from large urban areas) this indicates a need to control for spatial effects. though the relationship between population size and measles transmission has been the subject of many studies, previous e&w work has only focused on analysing data from urban districts, leaving a rich dataset of rural districts almost entirely untouched. we examine both spatial connectivity and within city measles transmission in urban and rural areas in locations in e&w. in a paper, bolker & grenfell examine the aggregate differences between urban and rural districts, using a subset of of these locations [ ] . much of the analysis in the paper examines the aggregate dynamics, combining case data from all urban and rural locations to compare timing and epidemic intensity. furthermore, the authors do not estimate epidemic parameters (such as transmission and susceptible population) from the data but rather compare aggregate urban and rural trends to an urban-rural patch model. these authors leave the question of spatial diffusion between urban and rural locations largely unanswered. furthermore, the authors note a strong spatial correlation across the e&w metapopulation and highlight the necessity of investigating these spatial patterns in greater detail [ ] . this paper investigates these differences at the individual district level and probes urban/rural differences at a fine spatial scale. we may expect to see differences in the disease ecology of urban and rural locations for several reasons. it is possible that the decreased population density in rural areas leads to a fewer contacts within these locations, resulting in slower transmission of measles in rural areas relative to their urban counterparts. variation in birth rates between urban and rural locations may impact transmission by replenishing the pool of susceptible individuals at different rates. differences in the number or size of schools-the primary location of outbreaks-may also impact the transmission of the disease. as susceptible contacts are generally driven by the school calendar, measles transmission in e&w typically has a consistent seasonality. we see peaks in transmission when students return from holidays, when susceptible populations are at their highest and when susceptible individuals are coming into frequent contact. if there are differences in the spatial proximity of schools we may see different transmission rates or different outbreak patterns. in particular, when schools are farther apart and mixing between them is relatively weak, we might observe either multiple small epidemics or slower progression of the disease through the district [ , , , ] . finally, if the migration or mobility of individuals occurs at uneven rates between location types, this may impact the probability of introducing new infections, and therefore spatial coupling estimates. if population movement between locations depends on more than just population size we may see differential case import frequency between urban and rural areas. for example, people may move between urban locations with more frequency than from urban to rural or between rural locations, in which case we will see lower estimates of spatial coupling in rural locations than in urban locations. we may expect urban to urban travel to be more common than urban to rural travel regardless of population size. for example, in the usa, covid- has been comparatively slow to spread to rural areas even as cases skyrocketed in urban areas [ ] . using estimates of transmission rates and spatial coupling, we compare all urban and rural districts. at the aggregate, we find a surprising amount of coherence: both internal dynamics and spatial coupling show consistent royalsocietypublishing.org/journal/rsif j. r. soc. interface : dependence on population size. we further restrict our sample to neighbouring urban and rural districts to isolate the potentially confounding associations between size, location and urban/rural designation. we find that size is consistently a more significant driver of epidemic dynamics than location type. the exchange of outbreaks between neighbours is dependent on population size, with larger locations frequently introducing outbreaks to their smaller neighbours. in this way, these mini-communities mirror national metapopulation epidemic cascades. however, we do find slight distinctions in the epidemic behaviour of urban and rural areas, namely that rural areas are characterized by more frequent outbreaks which infect fewer individuals. this suggests rural areas may sustain epidemics through internal rescue effects [ ] , and highlights the importance of accounting for heterogeneous mixing patterns to uncover subtle differences in epidemic spillovers. to explore differences in urban and rural areas, we analysed prevaccination weekly measles incidence data from to e&w [ , ] . this dataset is unusually rich, with urban cities and towns and rural districts. in addition, we used annual births, population and geographical location of each district. for the paired analysis, we use urban districts with a rural neighbouring district (for a total of districts). the classification of districts as urban or rural was not strictly scientific at this time. the system of the era involved a combination of considerations such as population density (measured in people per acre), level of urban development, and the type of local government (e.g. urban council or parish) [ ] . historical documentation indicates that this system of classification was at times arbitrary and resulted in a misclassification rate of approximately % according to contemporary standards [ ] . still, this classification is a feature of the dataset and likely represents some amount of structural difference between locations. additionally, if the misclassification occurred at random or resulted in more frequent classification of small sparsely populated districts as urban this would attenuate any differences we detect. additionally, we believe our strategy of selecting urban/rural districts will mitigate any potential misclassifications. as these are neighbouring districts with the same name that have been distinguished from each other by 'urban' and 'rural' labels, we expect the urban districts to be at least more dense than their rural neighbours, even if they are not dense in a global sense. in other words, though it is unlikely these data capture the global range of population density and sparsity, we do expect that neighbours will differ from each other. in fact, we were able to obtain land area for of the rural districts used in the paired analysis, and of the urban districts ( pairwise complete). we obtained these estimates from the wellcome trust (uk medical heritage archive); major boundary changes in necessitate obtaining land area estimates contemporary with the case data. for this subset of districts, the rural areas are consistently lower density (electronic supplementary material, figure s ). the least dense district is approximately . people per acre, and the most dense is about people per acre. while these do not represent global extremes of population density/sparsity, they provide enough variation to explore measles dynamics under different density conditions. incidence data were aggregated to the biweekly scale for modelling analysis (described below). the diversity of locations in terms of geographical space and population size, as well as the temporal detail of the incidence data provide an unparalleled and uniquely apt dataset for investigating urban and rural differences in transmission. the -year epoch covered by the data allows for a robust study of outbreaks as well as sufficient opportunities to compare urban and rural epidemics. furthermore, pre-vaccination data allow us to understand transmission patterns without uncertainty related to vaccination coverage, this provides the most direct estimates of transmission rates and mixing dynamics. the urban data used in this paper have recently been made available [ ] , the rural data and an r studio notebook to replicate the results of this paper are available in the electronic supplementary material. much of the analysis on the disease dynamics is done using the open source r package: tsir [ ] . we compared population dynamics and transmission within urban and rural using a number of metrics. we first examined epidemic fadeouts (time between epidemics) to see if urban and rural areas differ in the pathogen extinction rates. as these estimates may be subject to bias due to systematic differences in reporting rates, we also calculated the number and length of three-week fadeout which previous research has shown to be robust to under-reporting [ ] . we also computed average birth rates as well as the coefficient of variation in births. births may impact disease dynamics by altering the yearly influx of susceptible individuals. finally, directly from the incidence data, we calculated epidemic growth rates which we expect may correspond to differences in population mixing. to further assess local disease dynamics, we use a tsir model [ , , ] to obtain estimates of seasonal transmission. the tsir model is a discrete time mechanistic model where the susceptible dynamics can be modelled as the susceptibles at t + (s t+ ) are simply the previous susceptibles (s t ) plus births (b t ) minus the new infections (i t+ ). the associated deterministic infected dynamics are the seasonally varying transmission rate is estimated as β. the tuning parameter, α acts as a correction factor for moving from discrete to continuous time [ ] . in a purely theoretical sense α should be equal to unity in continuous time [ ] , however, discretized models produce more accurate predictions with α values slightly under unity [ ] . to be consistent with previous estimates for this dataset, we fixed α to be . [ , ] . the primary assumption of the tsir model is over a sufficient period of time, due to the high transmission rate of measles, everyone should acquire the infection. this allows us to assume that cumulative cases and cumulative births will be approximately equal, yielding an estimation of reporting rate. we can then reconstruct the susceptible population at each time step. with estimates of both the infected (reported cases divided by reporting rate) and susceptible dynamics, equation royalsocietypublishing.org/journal/rsif j. r. soc. interface : ( . ) can be log-transformed into a linear model from equation ( . ), we can estimate both the seasonal transmission rate (β t ) and an approximate measure of r (=β t n, where n is mean population size). we can also evaluate the seasonality by calculating the coefficient of variation in β t , this allows us to measure whether transmission is variable over the year or relatively constant [ , , ] . a full discussion of the implementation of tsir can be found in [ , , ] . a discussion of result sensitivity to estimation procedure (such as the regression type selected for susceptible reconstruction) can be found in the electronic supplementary material. additional information on model fit and parameter estimates across locations can also be found in the electronic supplementary material. the primary dynamic exchange of interest in this section is contact between susceptible individuals in a single district (local) with an infected individual from another district (regional), and whether such contact sparks an epidemic in the susceptible's district. in line with previous analysis, we include all other districts as regional, and thus we are estimating the epidemic coupling between one community and all other communities in our dataset [ ] . we use the reconstructed susceptible dynamics as well as estimates of β to calculate epidemiological coupling for each location. following extinction, the local dynamics are converted into a waiting time distribution, for which the probability that a fadeout will end is governed by the probability of contact between local susceptibles and regional infectives as well as the probability that an epidemic will result from such contact. spatial contact depends on the probability that a local individual is susceptible, the probability a regional individual is infected, and the spatial isolation of the local community ( /c j , where c j is the coefficient of coupling). we want to estimate the probability that contact occurs and that an epidemic is sparked. in other words: here, a is the probability of an epidemic occurring and b is the probability of contact between a local susceptible individual and a regional infected individual. in order to estimate the probability of an epidemic, we estimate the number of susceptible individuals at each time step as in equation ( . ). we use a modified version of equation ( . ) in which the expected number of infections is given by ( : ) i are local infected individuals and i are infections arising from regional contact, and β u is the seasonal transmission rate which corresponds to t. we expect β to vary within the year but to be relatively consistent across years for a single location j, thus it will fluctuate according to a biweekly indicator u, rather than continuously over time. we can model the trajectory of the epidemic as a piecewise-constant (at the scale of a single generation) birth-death process [ ] . if we assume a per capita birth rate in infections, in this case λ/(i + i), then starting with one infected individual the number of infected individuals in the following generation will be distributed according to a geometric distribution with expectation λ/(i + i). beginning with i + i infected individuals, we get a sum of i + i geometrics, it follows that the distribution of infections at t + as a function of infections at t is i tþ ,j negbin(l t,j , i t,j þ i t,j ): ( : ) negbin signifies a negative binomial process with expected value λ t,j , and a clumping parameter i t,j + i t,j . the probability of spatial contact between a local susceptible and a non-local infectious individual is modelled as Àexp (Àc j x t,j y t,k=j ): ( : ) the proportion of local susceptibles is x t,j and y t,k=j is the proportion of infectious non-locals, that is, the proportion of infectious individuals across all districts k which are not district j at time t. note that x j,t corresponds to proportions of susceptibles (s j,t /n j,t ), and y t,k=j is the proportion of infectious individuals ( p k i k=j,t = p k n k=j,t ). finally, c j is the coupling coefficient of location j. this coupling measure is analogous to other variants, such as the coupling coefficient of the population gravity model [ ] ; however, we use this non-parametric (with respect to coupling) version so our estimation procedure (as follows) can be guided by the epidemic data itself while minimizing a priori assumptions regarding population movement. given contact has occurred, the probability that an epidemic does not occur is given by /( + β t,j s t,j ), this is given by the null probability of the negative binomial distribution (equation ( . )) when i = and i = . an epidemic will occur by the complementary probability putting together the probability of spatial contact and the probability of an epidemic we obtain the discrete-time hazard this is an increasing function with the number of local susceptibles and the proportion of non-local individuals that are infectious, it may change with population size if isolation is size-dependent [ ] . conditional on the local susceptible population and regional prevalence of infection, the theoretical waiting time distribution can be written as the expectation of a binomial process for which the log-likelihood of the fadeout is given by the binary indicator z t,j is equal to if i t,j > and equal to zero otherwise, and h t,j is given by equation ( . ) . we sum over all observations for which the local infections remain at , up until an outbreak occurs. this allows us to calibrate c j by the moment an epidemic is sparked. this is an adaptation of the typical binomial likelihood function with the probability of an outbreak determined by h t,j (and thus the probability of no outbreak is ( − h t,j )). we sum over all observed outbreaks for each location and use newton-raphson maximum-likelihood estimation to obtain an estimate of c j from equation ( . ) . note that it is not possible to estimate c for those communities in which measles is endemic (i.e. there are no fadeouts). there were communities (out of ) that did not have a sufficient number of fadeouts to estimate the coupling coefficient, these locations are dropped from the coupling analysis but are included in the comparison of other measures of epidemic behaviour. in keeping with previous findings [ ] , we expect to see high coefficients of coupling for locations below the critical community threshold that are geographically proximate to larger districts which provide the reintroduction of pathogens. we expect small isolated areas to have the lowest estimates of coupling because imported infections as a result of human mobility will be relatively rare and thus the reintroduction of pathogens will have correspondingly lower probability. royalsocietypublishing.org/journal/rsif j. r. soc. interface : to illustrate the importance of spatial proximity more explicitly, we calculate the correlogram of incidence data across the entire dataset. this estimates the spatio-temporal correlation of the incidence data and its dependence on distance. we also examine districts within km of london. we calculate the correlation of incidence data for each of these districts relative to london and use a generalized linear model to estimate the association of distance, population size and district type on similarity to london's case data. probing differences further, we then subsetted our analysis to neighbouring urban and rural districts to isolate space from size and location type. these districts are adjacent and non-overlapping such that they allow us to control for spatial proximity and measure the relative influence of urban versus rural status and population size. these districts are sampled from a variety of spatial locations across e&w so the results are not a feature of a single area. we selected a representative sample of pairs (a total of districts) below the ccs and used principal components analysis (pca) to uncover the correlations between demographic characteristics (birth rates) and estimated parameters (susceptible fluctuations, transmission rates) and subsequently to see how urban and rural areas vary across these numbers. pca is the eigenvalue decomposition of the covariance matrix of scaled covariates. we scale the data so each variable column has zero mean and unit variance, this ensures variables with larger values are not given greater weight due to their higher variance. eigenvalue decomposition factorizes a matrix into its canonical form. it produces the vectors that (ranked by their eigenvalues) explain the most variance within the data. pca uses an orthogonal transformation to project a matrix possibly correlated covariates onto a new uncorrelated basis space. pca has been used to identify the genes that are responsible for the most populationlevel variation populations [ ] as well as to isolate dominant frequencies in complex signals [ ] . this method demonstrates ( ) how variables are related to each other, ( ) which variables are most influential in terms of looking for differences in the data and ( ) whether population size or urban/rural designation influence how locations score on these maximal variance vectors. pca enables an investigation of multiple variables simultaneously as well as isolating the importance of variables rather than testing each covariate separately. we withhold urban and rural indicators as well as population size so we can test their influence on the projections. after obtaining our principle components (eigenvectors), we project each location onto the first two principal components (the vectors responsible for the two dimensions of most variance). we compare each city's score with its rural neighbour to assess the influence of space. if space is the primary driver, we expect each location to be similar to its neighbour. we also compare the scores by population size. finally, we calculate the euclidean difference between each pair, this gives us a measure of how different each location is from its neighbour across the dimensions of highest variance. we then check the association of this distance with their difference in size. these comparisons together demonstrate the comparative influence of space, size and environment. we further attempt to disentangle the importance of district type by investigating the timing and duration of epidemics between pairs. many of the paired districts are small (median population ; range - ), and fitting the tsir model to locations can be challenging due to frequent and lengthy extinctions. making comparisons directly from the time series enables us to concretely measure timing and coordination of epidemics to assess how and if districts interact with each other. in particular, we evaluate the proportion of rural epidemics which occur during a simultaneous epidemic at its urban neighbour. similarly, we assess which member of each pair leads or lags in local epidemics. for each pair of districts, we evaluate the proportion of its epidemics which are preceded by an epidemic in it is neighbouring district. these proportions provide a measurement of how many epidemics can be attributed to the urban or rural component of each pair of districts. we also compare the total number of outbreaks and the number of large epidemics (greater than weeks) between pairs. investigating aggregate differences, such as epidemiological spatial coupling and fadeouts, between urban and rural districts, we find a consistent relationship with population size but no obvious difference by urban or rural designation. these findings are consistent with previous estimates for urban districts [ , ] . coupling increases log-linearly with population size for both urban and rural areas indicating that imports increase with population size (figure ). the analytical relationship between fadeouts, coupling, and population size is thoroughly investigated in bjornstad et al's paper [ ] . as population size increases, so too does the susceptible class, this increases sensitivity to imports and increases the probability of an epidemic. probabilistically, this increased sensitivity leads to fewer 'missed' epidemics and consequently reduces the proportion of fadeouts, even if import rates are consistent across locations. we are primarily interested to see if the advantages associated with increasing population size are different for urban and rural areas. figure would suggest the returns to population size are consistent. however, we know that the opportunity for imports also increases with proximity to endemic locations so to isolate the impact of urban and rural designation, we need to further control for this proximity. additional comparisons of tsir parameters such as transmission rate (β) and r reveal variation with population size, but urban and rural locations remain consistent (electronic supplementary material, figure s ). the proportion of biweeks without cases correspondingly decreases with population size for both urban and rural areas. however, figure further demonstrates the importance of spatial proximity to large metropolitan areas such as london, birmingham, manchester, liverpool and leeds in terms of both urban/rural designation as well as population size. figure b shows the spatio-temporal correlation of incidence in urban and rural areas across the entire dataset. we see that correlation decreases with distance for both urban and rural areas, though the urban decline is more precipitous. the spatial correlation of population size is approximately . for near neighbours but it falls below to statistically zero after about km. it is likely that population scaling as well as urban/rural distinction is a factor in this correlation. locally, population is spatially correlated; at the national scale, the correlation is smaller due to the number of small districts and parish between the largest urban centres. the correlation of incidence, population size, and urban/rural status is non-negligible (electronic supplementary material, royalsocietypublishing.org/journal/rsif j. r. soc. interface : figure s and table s ). this highlights the importance of controlling for these spatial features to assess differences in epidemic connectivity and infection dynamics between urban and rural districts. districts tend to be closer to districts of the same type (e.g. rural districts are closer to other rural districts) and large urban districts are more likely to have large urban neighbours. due to the importance of spatial proximity in regard to imported cases, it is necessary to isolate the effect of proximity from population size in order to further understand any potential urban and rural differences. for example, examining districts within km of london, we see a mean correlation in case reports of . . locations within km of london have an average correlation of . . using a generalized linear model, we estimate that an increase of km in distance is associated with a decrease in case correlation of − . , and an increase in population of individuals is associated with an increase in correlation of . (details available in the electronic supplementary material, table s ). this means that km of distance is comparable to a decrease in population of people in terms of the mean correlation with london. within km of london there are urban districts and only rural districts. these results indicate the importance of controlling for the spatial influence of large cities when comparing urban and rural districts. though we could attempt to investigate all locations in this way, it is a significant task to discover which large cities are influencing the epidemics for each district, particularly those in the hinterland, where many signals may mix and epidemics are comparatively rare [ ] . when we subset the data to the selected paired districts (mapped in figure a) we observe a modest difference between urban and rural areas when applying principal components analysis to the estimated parameters. this decomposition shows that the two most variable axes of difference are ( ) high coupling versus long fadeouts and ( ) variation in seasonal transmission versus growth rates. patterns of measles incidence show strong spatio-temporal correlation across e&w with a strong dependence on distance. while correlation of outbreaks is high among near neighbours, this correlation decreases rapidly with distance until about km where it slowly falls below the average temporal correlation for both urban ( . ) and rural ( . ) districts. the spatial correlation of all locations combined is consistent with these separate estimates. (c) analysing coupling as a function of population yields a strong log-log linear relationship across both urban and rural cities. this is consistent with previous findings we do not see significant differences between urban and rural areas controlling for population size. at the large populations, we see a large increase in the size of confidence intervals. this is due to the small number of interepidemic periods in large locations. with few opportunities to calculate coupling, the standard errors increase drastically. (d ) similarly, we find strong agreement between the urban and rural relationships for fadeouts and population. these figures demonstrate the importance of population size as well as proximity in determining epidemic dynamics. royalsocietypublishing.org/journal/rsif j. r. soc. interface : the first principle component (pc ) accounts for % of the total variance in the data (electronic supplementary material, table s ). it is an axis which measures the data with coupling at one extreme ( positive values) and fadeout length at the other (negative values). in other words, the spectrum which accounts for the most variance in the data is merely the separation of dynamics between locations which receive regular imports and demonstrate synchrony with the larger metapopulation, and isolated districts which experience long droughts of infection. the second component (pc ) explains % of the total variation in the data (electronic supplementary material, table s ). this component projects districts on an axis with variation in transmission (β) at one end (negative values) and growth rates on the other ( positive values). in qualitative terms, this suggests that epidemics generally exhibit rapid epidemic spread or strong seasonal variation in transmission. in other words, locations with explosive epidemics tend to have less seasonal variation, implying outbreaks are more randomly spread throughout the year. similarly, locations with more seasonal transmission experience epidemics which spread at a relatively slower pace. a district with a negative score on this axis will be characterized by high seasonality, indicating regular epidemics fed by relatively constant susceptible pools. a district with a positive score on the second component will likely have stochastic and explosive epidemics rather than annual or biennial schoolbased outbreaks (figure ). we observe slight and statistically insignificant differences between urban and rural districts. on average, rural areas have slightly higher coefficients of coupling compared to urban areas. conversely urban areas have on average fewer, more potent outbreaks. with regard to where districts fall on pc and pc , figure b shows districts either tend to have higher coupling estimates ( positive on pc ) accompanied by high variation in beta (negative on pc ), or long fadeouts (negative on pc ) and high growth rates ( positive on pc ). therefore, if we interpret the two-dimensional space created by pc and pc we see that the majority of variance in the data can be described as a spectrum from areas with strong epidemic coupling and consistent seasonality and one extreme and infrequent violent epidemics at the other extreme. this is consistent with previous studies of large and small urban locations [ , , ] . the space created by the first and second principal components has a plausible association with population size. we expect large places to receive more import cases and thus to have larger coupling estimates and shorter time between epidemics. we also expect large places to have more regularity in seasonal transmission as dictated by the school calendar, royalsocietypublishing.org/journal/rsif j. r. soc. interface : while smaller places are more vulnerable to random outbreaks. we also see that the largest outliers in the data (third quadrant) have long fadeouts and high susceptible population remaining after each epidemic. this suggests that a few locations in the data have very long interepidemic periods with few outbreaks which are not sufficient in size to diminish the susceptible population. this is consistent with previous studies of measles dynamics in e&w [ , , ] . principle component results demonstrate no statistically significant difference between urban and rural areas. when comparing adjacent districts we see district neighbours do not resemble each other (figure c,e) and that population is the main driver of differences both in terms of raw projections (figure b,d) as well as in determining the difference between urban and rural pairs (figure a). we classify the difference between pairs as the euclidean distance between the district's scores on the first and second principal components. we see that this difference is well explained by the per cent difference in population size. this suggests size, rather than space is the predominant driver of variation in disease dynamics. though urban and rural areas may not differ systematically, the analysis to this point does not describe how neighbouring towns and cities interact with each other. although pairs do not demonstrate coherence in their scores on pc and pc , we know infections move through space and expect to see some evidence of epidemic interactions between neighbours. in order to investigate these district pairs in more detail, we examine the case data directly. projections on the first component demonstrate that urban areas may have longer fadeouts and lower estimates of coupling than rural neighbours. since uncertainty around estimates of coupling can be large, particularly for larger districts, we examine the differences between urban and rural epidemics directly from the case data. consistent with the dynamics suggested by the results of pca, we find that rural areas fade out less and for shorter periods of time, resulting in more frequent, smaller epidemics (figure c,d). by contrast, urban areas are characterized by more regular short epidemics (figure c,d). urban and rural areas do not differ in the number of large (final number of infections greater than the mean) outbreaks, which increases consistently with population size for both district types (electronic supplementary material, figure s (b) ). we additionally find that larger districts tend to lead the epidemics of their smaller neighbours. the relationship between the difference in population and the proportion of epidemics lead in each location is strong (figure a). larger places appear to act as a importer of cases to their smaller neighbours, mirroring national patterns of epidemic spillover at a small scale. an example of such a pair can be seen in figure b . this suggests transmission cascades from larger places to smaller places in concurrence with previous findings [ ] , but replicated at a local scale. we do find a nominal, though significant difference between urban and rural areas particularly at smaller sizes. urban areas have fewer, larger outbreaks when compared to rural areas of comparable size ( figure c,d) . this difference is slight though statistically significant if we look exclusively at small areas. large urban and rural areas do not demonstrate a statistically significant difference. this indicates small urban populations may be nominally more well mixed than small rural populations. though this may seem intuitive and obvious it is important to keep in mind the crucial role of schools in measles dynamics. the population mixing rates relevant to this system are those of school-age children. these results therefore indicate that urban schoolchildren may be better mixed, with more cross-school mixing, than rural counterparts. alternatively urban areas may have fewer schools compared with rural counterparts, creating more concentrated contagion hotspots relative to rural districts. as a robustness check, we compare these same measures using population density for the subset of districts for which we have estimates. we see that differences in population density correspond well to final size estimates, but do not explain epidemic leads and lags (electronic supplementary material, figure s ). in particular, we see that denser areas generally have larger and fewer outbreaks, while less dense locations have more, smaller outbreaks. additionally, relative density shows no correlation with epidemic leads or lags. though these results represent only a subset of the paired data, they increase our confidence in the veracity of the small differences we observe. understanding how transmission may vary between rural (or sparsely populated) and urban (or densely populated) areas is a critical area of research in a rapidly urbanizing world. the united nations predicts that nearly % of the global population will live in urban areas by . though previous analysis on this unique detailed dataset has suggested measles transmission is size and density-independent with a strong seasonality in transmission and signature of contagion movement between locations [ ] , the urgency of contemporary changes necessitates a more complete understanding of potential differences across settings. previous analyses have been limited to urban areas. expanding this to include rural areas provides a more complete understanding of metapopulation dynamics and variation across space and urban/rural district type. the complete and rich nature of this dataset make it uniquely suited to be an initial case study for such investigations. this analysis shows that infectious dynamics are not uniform across locations. however, while we find an inverse relationship between infectious disease fadeouts and coupling of locations to the larger metapopulation, and between epidemic growth rates and seasonality, urban and rural locations follow the same pattern in spite of potential structural differences. although we see a slight difference on average between urban and rural areas when controlling for location and population, the overall patterns are consistent. population size is the most significant driver of epidemic dynamics (though total number of births is a comparable predictor and highly correlated with population size). additionally, while location does appear to impact dynamics, the similarity by pairs is not what we would expect if differences were entirely spatial (figure ). the difference in population sizes appears to explain many of the differences we observe. these findings are generally consistent with ferrari et al.'s results for nigerian measles epidemics [ ] . ferrari et al. find a rural/urban gradient characterized by reduced seasonal amplitude in sparsely populated settings as well as climatically royalsocietypublishing.org/journal/rsif j. r. soc. interface : driven contact rates. cross-location contact rates are even more sporadic in the nigerian context, indicating that much of the consistency between urban/rural locations in e&w is likely driven by a consistent seasonal forcing mechanism (school calendar) as well as more frequent cross-location mixing. in addition to confirming similarity between urban and rural areas, principal components analysis shows an important difference in large (above ) and small (below ) populations. larger places can be characterized by more frequent epidemics with a typical seasonal signature, while panels (c,e) plot urban and rural district pairs against each other on the basis of their scores on the first (c) and second (e) principle components. scores on or near the plotted line of identity indicate matching scores for the pairs. the score of an urban district has little to no relationship with the score of it is rural counterpart in general (c,e). however, as shown by (a) we see when pairs are of comparable size, they tend to have similar scores. if space had been the primary driver of epidemic dynamics, we would expect the points in figures c and e to follow the identity line. if pronounced differences existed between urban and rural locations, we would not expect pairs to look like each other or be well predicted by population size alone. the projection of the pairs on the first two components appears to be well determined by population size (b,d ) and the distance between each pair and its neighbour is well determined by the per cent difference in their populations. this would imply that spatial location has a marginal impact on epidemic dynamics and population size is a stronger driver of dynamics than urban or rural status. royalsocietypublishing.org/journal/rsif j. r. soc. interface : small places are characterized by stochastic epidemics which are slower and do not deplete susceptible populations. this confirms that small places inherit epidemics as spillover from bigger neighbours (figure ). when we investigate epidemic interactions between urban and rural areas we find size is the most important when determining which location will kick off a local epidemic ( figure ) . in other words, we see large scale metapopulation dynamics mirrored in these urban and rural pairs. the larger member of each pair seems to serve as an epidemic feeder for its smaller neighbour. in this case, it does appear to be size which drives the influx of cases rather than urban/rural status. the differences are most profound when population sizes are substantially divergent (on the order of - %). when urban and rural neighbours are of comparable size, there is no clear epidemic leader (figure ). on average, urban epidemics are contained within (in a temporal sense) their rural neighbour epidemics, % of the time; rural epidemics are contained within urban epidemics only % of the time on average. if we examine pairs for whom the urban location is approximately twice the size of the rural location, we see that % of rural outbreaks are contained within the larger urban outbreak. if we examine the converse, when urban areas are half the size of their rural neighbours, we see that % of outbreaks in these small urban centres are contained within those of their rural neighbours. urban figure . epidemic interactions among neighbouring urban and rural districts. (a) the per cent of the population difference (relative to the urban district) compared to the proportion of epidemics led by urban or rural district. we see for both rural and urban areas, the per cent of epidemics led increases as the per cent difference in size increases. this confirms previous findings that large areas provide epidemic spillover to proximate smaller areas, this highlights the cascading effect of epidemics at a local level. (b) guilford provides an example of this subtle dynamics wherein an urban area has fewer small outbreaks and larger major epidemics even when the neighbours are of similar sizes. the dotted lines indicate the average final outbreak size ( total average infections for the urban district and for the rural). in the case of guilford, both the urban and rural district have outbreaks, the rural district has larger outbreaks while the urban district has . these larger rural outbreaks are smaller in terms of final size than the outbreaks in the urban district. (c) rural areas have more outbreaks than urban areas of comparable size. (d ) mean final size of outbreaks for urban and rural areas (log scale) with standard errors. rural areas tend to have smaller outbreaks on average, though the standard errors are large and the difference is not statistically significant. royalsocietypublishing.org/journal/rsif j. r. soc. interface : size in a competing destination's framework of receiving imported cases. it may indicate that the increase in receiving cases as a result of increasing population size is greater for urban areas than for rural areas. in other words, larger urban areas are marginally more attractive for cases than rural counterparts. it is also sometimes the case that rural districts completely or mostly surround urban neighbours, for these districts early rural outbreaks may be the result of incidental rural infection en route to urban districts. however, more explicit data on population movement patterns, particularly those of children, are necessary to verify this argument. it is also possible that epidemics in urban districts create multiple rural echos, producing multiple smaller epidemics. controlling for population size, we observe a small though statistical significant difference in epidemic behaviour between urban and rural districts (electronic supplementary material, figure s ). rural areas have more frequent, smaller outbreaks while urban neighbours have relatively fewer, larger epidemics. this confirms previous findings that aggregated urban dynamics showed more intense epidemics relative to aggregated rural data [ ] . here, we have explicitly shown this behaviour at the district level, controlling for space and proximity to large cities. to verify this behaviour with known population densities and mixing rates, we simulate epidemics in a number of communities. we vary the total size, number of patches (as a proxy for multiple infection hotspots), and mixing rates between patches. we then examine fadeout proportions and final sizes across a combination of patch numbers and mixing rates for each community size (figure ). we assume the population and birth rates within each patch are equal and the within-patch transmission rate is constant for an r of , a reasonable estimate for measles [ ] . across-patch transmission rate is fixed at %, %, %, %, %, % and % of the within-patch rate. from the simulated incidence data, we calculate the average number of fadeouts and the average final size of outbreaks. as expected, increasing patches reduces the final size of each epidemic and reduces the fadeout proportions. additionally, increasing the across-patch mixing rate increases the final size and increases the proportion of fadeouts. this is congruent with the slight difference we observe between small urban and rural districts. the across patch mixing rates were reduced such that they represented a fraction (given by the 'across' axis of the internal mixing rate. (c) example time series for a population of with an across patch mixing rate of % of the within patch mixing rate. cases are shown for sample simulations with two and eight patches. within patch mixing rates were held constant to produce an r of , a typical estimate for measles. simulations show the number of outbreaks increases as the number of patches increases (b) and the final size of the outbreaks decreases as the number of patches increases (a). in addition, as mixing rates between patches increase, the proportion fadeout biweeks increases and the final size increases. this supports the conclusion that rural areas may be characterized by patch mixing with relatively weak mixing between leading to more, smaller outbreaks when compared with urban counterparts. heterogeneous contact patterns in rural areas may be driving these subtle differences relative to urban areas which may be closer to well mixed. rural districts may have several transmission hotspots (schools) distributed over a greater area. strong within-school mixing coupled with weak across school mixing rates would result in multiple small outbreaks. by contrast, a denser urban area will provide more opportunities for mixing even when multiple schools exist leading to fewer, larger outbreaks, as demonstrated by the simulation results in figure . school-level data are crucial for further disentangling differences between urban and rural areas. specifically, school data could elucidate whether rural areas are receiving more cases than urban areas or if multiple hotspots are producing multiple epidemics from within the community. however, to our knowledge adequate data for this time period does not exist in an appropriate scale to address this question. furthermore, even if we optimistically assume urban and rural designations are substantive in these data, it is also true that urban and rural distinction in e&w is not comparable to global differences in urban and rural environments. that is, rural areas are denser than global rural extremes and urban areas are smaller and less dense than contemporary megacities. despite this, our exhaustive analysis of urban and rural disease dynamics in this detailed dataset provides a strong first examination of possible differences. an additional challenge in this context is the age profile of the susceptible class (typically schoolchildren, aged between and years), as well as the primary transmission location (schools). the movement pattern of schoolchildren is unlikely to exhibit as much variation in mobility or contact rates across contexts; this may be especially true in e&w during this time period where school attendance is compulsory for young children. as the majority of contacts for this age group occur in school settings, there is likely not as much variability in these contact rates in urban versus rural settings relative to other types of contact. extrapolation of these findings to other contexts is limited to acute immunizing pathogens in countries of similar levels of development. however, we would expect the differences to be more pronounced in countries with more variation in urban/rural settings. though it is likely that the districts in this dataset do not adequately reflect urban/rural differences in other countries, the methods in this paper may serve as a useful framework for urban/rural analysis in other contexts. in the wake of contemporary measles outbreaks and declining vaccine coverage, comprehension of measles transmission has gained renewed urgency. understanding transmission over metapopulation structures is vital for predicting outbreaks and planning interventions. additionally, understanding the spread of disease over different population densities and mixing patterns is crucial in a rapidly urbanizing world. this analysis illustrates the cascading of disease transmission even at local levels, suggesting the larger of two populations is at greater risk of infection holding geographical location relatively constant. furthermore, it suggests transmission may be slightly more rapid in dense areas but that persistence may be greater in sparse areas. the strength of transmission across locations highlights the potency of measles infection across scales. in addition, case data demonstrates that infections cascade from endemic areas to places of next-largest size, and that this pattern persists even at extremely local scales. in general, this suggests the importance of targeting interventions in large population centres were disease outbreaks can grow to epidemic levels and instituting control strategies to prevent disease from travelling to subsequent locations. finally, results on rural transmission highlight the importance of understanding local population mixing patterns and maintaining records on the number and spatial distribution of community hotspots. further research is necessary to build a comprehensive understanding of transmission in urban and rural areas. in particular, more detailed data on population densities within urban/rural areas as well as mixing patterns will be critical in untangling the pace and persistence of epidemics. in particular, similar studies in contexts with greater variation in urban and rural settings could help elucidate the impact of density on mixing rates for this particular susceptible class. in addition to highlighting slight differences between urban and rural districts within a metapopulation, this work demonstrates the importance of the spatial scale of reporting for estimates of disease transmission. aggregating several transmission zones into one reporting region may reduce estimates of contagion and overestimate import rates. data accessibility. the data and code necessary to replicate the findings presented in this paper have been included as electronic supplementary material. measles control in sub-saharan africa: south africa as a case study measles resurgence in belgium from january to mid-april : a 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outbreaks in the european alps acknowledgements. many thanks to ottar bjornstad and alexander d. becker for input, edits and advice on the project. key: cord- -o ogmg authors: robertson, lindsay j. title: the technological 'exposure' of populations; characterisation and future reduction date: - - journal: futures doi: . /j.futures. . sha: doc_id: cord_uid: o ogmg the nature and level of individuals' exposure to technological systems has been explored previously and is briefly restated here. this paper demonstrates how the concept of technological exposure can be extended to generic needs of individuals, and further to the needs of populations of individuals and even as far as “existential threats” to humanity. technological categories that incur high levels of population exposure are explored, and categories are described. a theoretical basis for reducing population exposure is developed from the basic concepts of technological exposure. technological developments that potentially enable less centralised societies having lower levels of population exposure, are considered for practicality and effectiveness as are the factors that could allow and cause transition to a less technologically centralised model. some conclusions regarding practicality, triggers, and issues arising from a decentralised society are considered and include the key conclusion that a higher level of decentralisation and exposure reduction is both desirable and possible. the fundamental impossibility of never-ending growth have been recognised for a long time (e.g. daly , henrique et al. ) and similarly authors (e.g. rao ) have recognised the danger of corporates of transnational size. this paper considers an associated but distinct issue, the growing technological vulnerability of populations. increasingly, essential goods and services are only accessible via technological systems that are both sophisticated, and also centralized. in this situation, end-user technological vulnerability becomes significant, but quantifying the extent and nature of such vulnerabilities have been hindered by the complexity of the analysis (haimes & jiang the supply of essential goods and services will involve heterogeneous systems (i.e. systems where goods/services are created by a progression of steps, rather than a system in which completed goods are simply transported/distributed), that involve an arbitrary number of linked operations each of which requires inputs, executes some transformation process, and produces an output that is received by a subsequent process. four essential principles have been proposed (author ) to allow and justify the development of a metric that evaluates the contribution of a heterogeneous technological system, to the vulnerability of an individual (author a). these principles are: ) the metric is applicable to an individual end-user: when an individual user is considered, not only is the performance of the supply system readily defined, but the relevant system description is clearer. ) the metric acknowledges that events external to a technology system only threaten the output of the technology system if the external events align with a weakness in the technology system. if a hazard does not align with a weakness then it has no significance. conversely if a weakness exists within a technological system and has not been identified, then hazards that can align with the weakness are also unlikely to be recognised. if the configuration of a particular technology system is changed, weaknesses may be removed while other weaknesses may be added. ) the metric depends upon the observation that although some hazards occur randomly and can be assessed statistically, over a sufficiently long period the probability of these occurring approaches . . the metric also depends upon the observation that intelligently (mis)guided hazards (i.e. arising when a person j o u r n a l p r e -p r o o f intentionally seeks a weakness in order to create a hazard) do not occur randomly. the effect of a guided hazard upon a risk assessment is qualitatively different from the effect of a random hazard. the guided hazard will occur every time the perpetrator elects to cause the hazard and therefore such a hazard has a probability of . . ) the metric depends upon the observation that it is possible to not only describe goods or services that are delivered to the individual (end-user), but also to define a service level at which the specified goods or services either are or are-not delivered. this approach allows the output of a technological system to be expressed as a boolean variable (true/false), and allows the effect of the configuration of a technological system to be measured against a single performance criterion. applying these principles, the arbitrary heterogeneous technological system supplying goods/services at a defined level to an individual, can be described by a configured system of notional and/or/not functions. having represented a specific technological system using a boolean algebraic expression, a 'truth table' can be constructed to display all permutations of process and stream availabilities as inputs, and technological system output as a single true or false value. from the truth table, a count of the cases in which a single input failure will cause output failure, and assign that total to the variable "e ". a count of the cases where two input failures (exclusive of inputs whose failure will alone cause output failure) cause output failure, and assign that total value to e . a further count of the cases in which three input failures cause output failure (and where neither single nor double input failures within that triple combination would alone cause output failure) and assign that total value to the variable "e " and similarly for further "e" values. the exposure metric, {e , e , e …}, for a defined system supplying specific goods/services, can be shown to measure the level of vulnerability of the individual to that technological system (author ). for many practical cases a generic service could be considered -e.g. "basic food" rather than "fresh milk", and vulnerability assessed by nominating multiple specific services as alternative suppliers (an "or" gate) of a nominated generic service. the exposure of the individual to lack of secure access to the necessities of life, can thus be assessed using exactly the same approach used to assess exposure to nonavailability of any specific need. illustrative examples of generic services could include "all needs for maslow's physiological level". conceptually this would include ((food_a or food_b or food_c…) and warmth and water and shelter) or possibly "all needs to occupy apartment on month-by-month basis". (sewage services and water supply and power supply). the concept of an individual's exposure may be yet further modified and extended to consider the quantification of a population's exposure, in regard to supply of either a particular, or a generic service. it is common for some "population" to need the same services/goods, and obtain these via an identical technological system. the "technological system" that supplies such a population may not be identical to that which supplies an individual: consider a case in which four individuals each rely on their cars to commute to work; for the output "arrive at work", each of their individually-owned cars contribute to the e exposure of each of the individuals. if they reach a car-pooling agreement, the "car" then contributes to the e exposure for j o u r n a l p r e -p r o o f "arrive at work" of each individual, since any of the cars can supply that functionality. a population exposure is developed by modifying an individual exposure evaluation (for a population using a functionally identical service) by considering each functional element used by more than one of the population, and whether each such functional element can be made accessible to more than one. if an exposure level (metric) is then nominated, it is possible in principle to establish the largest population which is subject to this level of exposure. for example, we might identify the largest population using a functionally identical service or supply of goods, that has a non-zero e exposure (i.e. has at least on single point of failure): should a city discover that the progressive centralisation of services had resulted in a situation where the whole population of the city had a non-zero e value for an essential service, some urgent action would be strongly suggested. conversely, if the supply of generic service to even small suburbs had low exposure values, then a good level of robustness would have been demonstrated for that generic service, at the suburb level. extrapolating these principles, where a "population" is actually the totality of the homo-sapiens species, and the "service" is essential for every individual's survival, then a definition of "existential threat" as proposed by bostrom ( ) , is approached. the analysis of exposure considers loci of failure and hence intentionally avoids consideration of specific hazards or their probabilities. nevertheless, hazards that affect various populations certainly exist, and a short list will serve to illustrate the significance of evaluating population exposure levels. the following list makes no attempt to be comprehensive, but illustrates hazards relevant to large corporates, j o u r n a l p r e -p r o o f apartment-dwellers, members of isolated communities and users of electronic communications.  a large group could be criminally held to ransom by malicious encryption of essential data (pathak ) .  a large group could be effectively excluded from access to a service because of conditions imposed by a (single, national) owner (tanczer, et al. , deibert , sandywell .  an isolated group (on antarctica, moon or perhaps mars) could cease to be viable if they cannot import supplies that cannot be generated locally (p?kalski & sznajd-  the occupiers of an apartment block could encounter a situation in where there was minimal (financial or other) pressure on the provider of sewage removal services to restore service, but where the occupiers faced major consequences (need to de-camp) in the absence of this service. similarly, (author a) has noted that a failure to provide financial transaction services to a small retailer may incur negligible financial cost to a bank, but may cause the retailer's business to fail. these are examples of asymmetric consequences.  the whole of humanity exists on the planet earth: a failure of the natural environment can doom either a regional or possibly a global population (diamond ) , and can be certainly be considered to be an "existential threat", as defined by bostrom ( ) .  persons born early in the th century were very familiar with the possibility of highly unjust treatments (e.g. loss of employment), if private information became known -and they acted accordingly. for many born early in this century, such concerns seem remote. personal information privacy issues have thus failed to gain a j o u r n a l p r e -p r o o f high visibility, and we have perhaps become blasé about the costs of lack of privacy. nevertheless, the ubiquity of surveillance (miller , citron & gray , the increasing frequency of major data breaches (edwards et al. ) , and the recent rise in algorithmic decision-making (moses ) on such matters as health insurance, credit worthiness, validity of job application and security targeting are bringing this issue to increased prominence.  the recent revelation of hardware vulnerabilities in general processors (eckersley & portnoy , ermolov & goryachy ) demonstrated the significance of unappreciated weaknesses, even when overall operation of a system has been reliable. other publications (author , martin have noted society's vulnerability to technological systems and considered the relationship between time-todisaster and time-to-repair: that analysis was not an exposure analysis, but did consider the range of services corresponding to a broad category of human needs and effectively considered the significance of the exposure categories noted above. later works (author a) have analysed the individual exposure associated with a broad range of goods and services. those works also noted that the analysed values for these specific examples could be reasonably extrapolated to many other similar goods and services. the general analyses of (author ) did attempt to cover the scope of individual needs and as such identified a range of services (or goods-supply needs) that were considered to incur high levels of vulnerability. the more detailed exposure analyses of (author a) were indexed to the exposure of an individual, and although a limited number of examples were studied, these were considered to be representative of the high-exposure items relevant to j o u r n a l p r e -p r o o f individuals living in urbanised settings in the st century. the assessment of the population exposure of those exemplar technological systems shows several distinctive changes from the analysis indexed to the individual. primarily, the e items that arise close to the final point of use by the individual lose significance and for many cases cease to be significant at the e level (arbitrarily chosen as the cut-off point for consideration). the components that remain significant are those that genuinely represent exposure values for the population under consideration. the analysis of population exposure of a broad spectrum of needs showed that it was possible to identify some high exposure technological fields, specifically complex components, complex artificial substances, finance, communications, energy and information, these are considered more fully as follows;  complex components: complex components may be distinguished from large components (such as a building, hydroelectric dam, or road-bridge), and qualitatively described as being beyond the capacity of a skilled individual craftsperson to fashion in reasonable time and to required tolerances. under this category we might consider such items as a carburettor body for an internal combustion engine, food processing equipment and construction machinery (crane). for many consumer items within the "complex component" category, the population exposure is significantly lower than the individual exposure, since numerous examples of item exist (either owned by others, or stockpiled for sale). the level of centralisation may however be very high, with (for example) perhaps only one worldwide source of a carburettor body for a specific vehicle.  complex artificial substances: complex artificial substances includes advanced metallurgical alloys, advanced plastics and composites, drugs, and vaccines: these j o u r n a l p r e -p r o o f are distinguished by the complexity of composition, rather than complexity of form. in many cases the centralisation that causes high exposure levels for the production of complex substances, has resulted primarily from available economies of scale, and only secondarily from the substances' complexity. some complex substances (notably pharmaceuticals) have patent protection, which creates centralisation at up to global level.  finance: as the range of goods and services, and the geographical scope of supply of those goods and services has increased, so has the need for the facility to exchange value in return for goods and services: this has inevitably led to elaborate mechanisms for secure exchange of value. recognising that the exchange of value can also facilitate illegal activities, state actors have also enacted significant surveillance and control of financial transactions. technologies associated with the exchange of value have acquired high large levels of exposure (colloquially, many things that can go wrong) and high levels of centralisation, in the process of meetings these demands.  communications: the ubiquity of the internet has become a remarkable feature of the last years: although there are exceptions, most areas of the earth and a very large proportion of total population can communicate via internet. although cellphone use is common, it is evolving as a mobile access connection, with the internet carrying the data. internet communications has been made possible by wellestablished protocols, however high level systems for routing continue to be centralised, and while problems are rare, nation-states have occasionally decided to discontinue connection to the internet, showing that high levels of centralisation exist (howard et al. ) . although the feasibility of internet communications can be attributed to open source protocols, the practicality of current connectivity has been j o u r n a l p r e -p r o o f largely enabled by the very large data rates possible via fibre-optic cables, yet this capacity has also introduced a high level of exposure for both individuals and populations. duplication of undersea fibre-optic cables has somewhat reduced the level of population exposure, yet the trend for dependence on high-data-rates has increased at similar pace (market forces have driven the need for additional cables), and communications via internet carry a high level of population exposure. recent reports (rose , clark have noted that the disruption of a very small number of fibre-optic cable would lead to unacceptable slowdowns, and trends to ownership of undersea cables by corporate entities further contributes to e values of exposure and high population exposure. the numbers of cables in service show that internet communications is centralised at a small-nation level.  energy: energy has been noted as key to civilisation (smil ) . coke allowed the smelting of iron, and oil enabled almost all current transportation. coal, nuclear and geothermal heat and hydro storage allow electricity generation on-demand. national power transmission systems generally have high reliability and many have some level of design redundancy. nevertheless, the generation and distribution of electric power incurs significant individual and population exposure: large power stations are bespoke designs as are large transformers (sobczak & behr ) , and transmission networks may face significant "resilience" issues (carvajal et al. , sidhu . liquid fuels can be stockpiled at national level, and to a lesser extent locally, however the level of stockpiling is limited -and even the higher levels of stockpiling are likely to be small compared to the time to rebuild a major production plant (terminal, or refinery). at the consumer and industrial user-level, although solar pv and wind can produce power at $/kwh rates close to thermal generation, but currently no economically viable technology that allows storage of megawatt-hours  information: information, whether medical reference information, contractual records or engineering design information, is not a coincidental by-product of a technological society, it is information that fundamentally allows the design and construction of technological systems and to the full operation of society (dartnell , shapiro , van den heuvel ). yet while it has become possible to generate and transmit enormous quantities of information, the information storage remains a particularly high-exposure issue (bergeron ) . currently the ascii codes largely standardise information representation, and protocols for transmission are also largely standardised but a gap in the standardisation of information storage (including writing and recovery) contributes to a high exposure for the final delivery of information to users. hard-disk drives are still the most common storage technology, yet these have short lives, and use proprietary data storage formats plus proprietary approaches to the writing and recovery of data. this issue has been wellreported, authors such as (cerf ) have predicted a "digital dark age", i.e. a future society that cannot recover/read most of the information generated in the current era. this describes a situation of high individual and population exposure, and since there j o u r n a l p r e -p r o o f are few of manufacturers of hdd's, information storage can also be noted to illustrate centralisation at multi-nation level. several technologies allowing longterm storage have been proposed (kazansky et al , longnow foundation; nanoarchival™ technology) but these are currently expensive and lack the integration to allow them to truly offer changes to population exposure. by contrast, some fields have generally low population exposure: basic building materials, foodstuffs, natural fabrics and clothing are commonly supplied via relatively simple technological systems in which technological design redundancies are commonly large, and for which population exposure is therefore low. technologies such as creation of ceramics and glassblowing may require skill but are also not dependent on high technological sophistication and so contribute low technological exposure. similarly, the collection and storage of rainwater is feasible with low technological exposure for even densely populated urban populations. in addition to identifying high exposure fields, it is also possible to identify categories of exposure contribution that commonly apply across a range of technological fields. these are proposed to include initial resource availability, complex unit operations, lack of buffering, single points of failure (spof), contributory systems, highly centralised processes and "practical unavailability", and are described more fully as follows: initial resource availability: all technological systems producing goods and services for users, ultimately depend upon raw materials and viable environmental conditions. where raw materials cease to be available, or environmental conditions change permanently, services to users will inevitably be affected. raw material supplies and acceptable environmental conditions must therefore be identified (diamond ) j o u r n a l p r e -p r o o f as sources of exposure and hence vulnerability to users. complex unit operations: we use the descriptor "complex" as a characteristic of a process whose internal operation is practically unknowable to the user and cannot realistically be repaired by the user. personal computers, routers and related equipment are examples. it is also possible to consider situations where a critical application has been compiled from an outdated programming language and runs on a computer for which no spare hardware is available (hignet ). another example might consider critical information held on a very old storage medium (teja ) . these examples illustrate three categories of complex processes: in the first case, while the inner workings of a pc may be exceedingly complex, the format of incoming data (tcp/ip packets) and protocols (www, email etc.) are in the public domain (fall & stevens ) and so it is not only possible but practical for alternative machines to offer the same services. in the second case, assuming the functional specifications of the application processes are known, the application can be re-coded (and fully documented) using a language for which larger numbers of maintenance programmers exist, and on a more common platform. the third case of data encoded on old storage medium, illustrates a subcategory where the internal details of the storage are proprietary (not in public domain), alternative equipment is unavailable, and creation of replica equipment for reading the data is probably impractical, leading some authors e.g. (cerf ) to express fears of a "digital dark age". lack of buffering: for the supply of long-life products, it is both possible and practical to provide buffer stocks at various points in the process. by contrast, since ac power (for example) is not readily storable, all processes involving uses of ac power will fail immediately if the power supply fails. single points of failure (spof): all single points-of-failure (spof) contribute to e values and so make a primary contribution to users' vulnerability. three subcategories of spof are noted: the first is j o u r n a l p r e -p r o o f where delivery of services to users involves some processes immediately adjacent to the user, known as "last mile" services in the telecommunications field. the second subcategory of spof is illustrated by considering a small rural town whose eftpos, landline phone service, cell-phone service and internet connection have all been progressively migrated to data services, carried by a single fibre-optic cable and thus have inadvertently created a spof. the third is where a particular failure will inevitably cause failure of other components that are not functionally connected -a cascading failure. finally it is noted that contributory systems are a common source of exposure: whenever a system is made dependent upon another, the contributory system's exposures are reflected in the total exposure to the user. a common example is where a simple user service is made dependent upon internet access; the mandatory internet access may add huge levels of exposure to a system that would otherwise incur low levels of vulnerability. some specific technologies including artificial intelligence, nuclear weapons and asteroid strikes have been examined, and authors such as baum ( ) have pondered their potential to incur existential threats by threatening multiple systems. others including baum ( ) and green ( ) have considered approaches to limiting the scope of such hazards. the above categories of exposure may apply to any technological process; there are additionally several categories that are specifically relevant to the study of "population exposure", these include highly centralised processes, for example, the evacuation and treatment of sewage requires a network of pipes and pumps to collect sewage and deliver it to the treatment station. this is an example of a centralised system that is large but technologically simple. other examples of large centralised systems include financial transaction systems (o'mahony et al. ) , and the international data transmission systems of undersea fibre-optic cables (clark ) . such systems tend to j o u r n a l p r e -p r o o f be monopolies and are commonly controlled by entities that have little if any obligation to provide service or to negotiate terms acceptable to individual users. authors such as li et al. ( ) have shown that highly interconnected systems have similar characteristics to centralised systems, and it is well-recognised that the most "centralised" system is earth's natural environment, because the natural environment (including air and water) are essential to all life. practical unavailability: consider the hypothetical case where a user wishes to communicate sensitive information, but only has access to one data transmission facility that is known to be under surveillance. although technically operational, the inevitable absence of privacy associated with that data transmission facility has made the facility practically unavailable. for technological systems that are highly centralised and near-monopoly, practical unavailability is a significant possibility. the en metric has been explained earlier in terms of its significance for measuring vulnerability, however a wider and more future-oriented applicability of the metric itself can also be demonstrated in several ways. the assumption that there is an average cost of defending any vulnerability could be challenged but across a broad enough spread of examples, it is workable. under that broad assumption, whereas the cost of defence for an e exposurecontributor is precisely the same as the cost of defence for a contributor to an e vulnerability (it is the cost of protecting one only vulnerability, since the e contributor requires successful attack of all three vulnerabilities), the cost of mounting a successful attack on a e vulnerability is times greater than the cost of attacking a vulnerability j o u r n a l p r e -p r o o f contributing to the e value, since the attacker needs to identify and successfully attack all e -contributory nodes simultaneously. in addition to its value for measuring vulnerability, the exposure metric is therefore also broadly significant for planning the reduction in vulnerability of a system. considering the generation of an exposure metric, the process itself provides valuable insights into options for reduction of the final values. the process of generating an exposure metric must be started from the delivery point, and follow a systematic redrawing and track-back process until a justifiable end-point is reached. the selection of a justifiable end-point has been addressed elsewhere, and could be associated with "no further contributors to an en level" criterion. the process of achieving a final representation of the system will very likely require a progressive redrawing of stream and process relationships; an example of a common re-drawing is presented in figure . in a practical process of building an exposure metric, subsystems (which may have been analysed separately) commonly contribute goods or services to "higher" systems. if the exposure metric of a subsystem is known then there is little value in recreating a truth table for a higher level super-system, that re-explores all of the inputs to every sub-system. the more-effective approach is to consider the point at which the subsystem output contributes to the input of a gate within the higher level system, and how the subsystem exposure metric is transmitted/accumulated by the upstream gate of the super-system. we may generalise this process by considering that each input to a gate (boolean and or or operation) has an exposure vector, and developing the principles by which the gate output can be calculated from these inputs. this is illustrated in figure . for the and gate, the contributory exposure vectors are simply added. for the or gate, the issue is more complex, but the higher levels of exposure are quickly avoided. the process of generating the metric will itself highlight sources of large exposure, and hence specific options for reduction. the detailed process for analysis of exposure has illustrated how the e values are accumulated and how specific exposure reduction options may be identified. generalised approaches to the reduction of the exposure of a population can also be identified. the process of redrawing shows that even where alternative subsystems can supply higher systems, if there is a locus of weakness that is common to alternative subsystems, the exposure analysis will ensure that such facts are preserved and the e contribution will actually appear in the exposure value for the whole target consumer (group). if the "o" ring seal failure had been identified as a contributor to the e j o u r n a l p r e -p r o o f exposure of the thiokol solid booster rocket then the elimination of all e values for the parent system that was the challenger space shuttle, could not have been achieved unless the "o" ring weakness were addressed. the use of an exposure metric therefore potentially addresses the colloquial saying "it's always the smallest things that get you". one of the learnings from the analysis of the "challenger" tragedy was that even known subsystem weaknesses could become lost as analyses were progressively summarised. when genuinely independent, alternative sources are available, their effect on the next-highest systems (process, consumer or group) is illustrated by the operation of an "or" gate. if genuinely independent/alternative subsystems that each have exposure vectors with non-zero values of e , are combined via an "or" gate, the higher system does not see any exposure at above the e level from that source. this principle might be qualitatively or intuitively perceived, but the effect upon an analysis of exposure provides a starkly quantitative analysis. it may also be observed that while reducing the exposure of each subsystem would require separately addressing each contributor to the subsystems e , e and e values (potentially a major task), if genuinely alternative subsystems exist then the combined "or" exposure has no nonzero contributor more serious than e and may warrant no further action. whereas many th century devices were designed for a single purpose and high throughput (mass production), some recent trends have been to devices that can be repurposed -and the pinnacle of flexibility is the human being! for any case where a piece of equipment contributes to the e value (is a single point-of-failure), if the capability of that equipment were able to be undertaken by multiple options (e.g. j o u r n a l p r e -p r o o f alternative human operators), the exposure contribution may be reduced to the en level, where n is the number of alternatives or persons capable of undertaking the equipment's function. an illustration may help to clarify this principle: if a sensor provides input that is required by an upstream function, that upstream function and all higher dependencies are exposed to the capability of the sensor to provide input: if 'n' humans are able to provide their best assessment of the sensor's input, then the exposure of the higher system to that functionality is reduced to the en level. considering the high-exposure technological fields that were identified earlier, generalised approaches to reducing the accrued actual exposure include standardisation of specifications that allow competitive supply of complex components and complex substances, avoiding the large exposure of some contributory systems, retention of genuine alternatives (e.g. cash/gold as well as electronic transactions). there is an intuitive appreciation that it is undesirable to have high vulnerability levels for systems that affect large numbers of persons. some may also intuitively appreciate that trends to centralisation, driven by economies of scale, increases the technological vulnerability of large population groups. the analysis of population exposure and the principles of exposure analysis therefore provide a quantitative approach that can be used not only to assess the level of exposure of current systems, but more importantly to show quite widely applicable principles for exposure reduction. specifically the analysis shows that centralisation of production almost inevitably j o u r n a l p r e -p r o o f creates higher population exposure values, and provides a sound theoretical basis for promoting decentralisation of production as an approach for the reduction of population exposure. it is important to consider the practicality of population exposure reduction by decentralisation; this is reviewed within each of the fields previously identified as incurring high exposure: a) complex components. in order for this functionality to be genuinely available at a significantly decentralised level, we can consider the sub-systems that are required, and the current level of maturity of technology options within each of those subsystems. for a complex component, relevant subsystems include those associated with the supply of materials and the creation of complex shapes from basic material stocks. for many cases, assembly of components is likely to be straightforward but we must also consider cases where assembly itself requires specialised equipment. for the majority of cases, the composition of the complex component can be assumed to be uniform, however cases where composition is not uniform (e.g. multilayer circuit board) must also be acknowledged. equipment for additive and subtractive manufacturing is available; specifically d printing equipment is readily available at small scale, and large scale implementations (bassoli et al. , kraft et al. ) have been tested. a moderately standardised format for d printer design information exists as iso - : , and iso : (many sections) , and instructions for operating additive and subtractive manufacturing equipment are such that high skill levels are un-necessary. a significant body of designs (pinshape™,  complex substances. in order for complex substance synthesis to be genuinely available at a significantly decentralised level, we can consider the types of complex substances that are of interest, the sub-systems that are required for each, and the current level of maturity of technology options within each of those subsystems. broadly, the complex substances could be categorised as: complex alloys, complex inorganic liquids (oils, detergents, etc.), complex organic materials (pharmaceuticals, insecticides, herbicides), complex substances derived from living organisms -yeasts, vaccines, fermentation bacteria, and polymers. for a complex molecular substance, it is currently common for a range of supply chains to bring raw materials to a synthesis plant. a sequence of synthesis steps (including unit operations of heating and cooling, separation, reaction, precipitation and dissolution) are carried out to generate a complex substance. for "organic" compounds, temperatures are generally limited to below ºc. for a complex metallic component, it is currently common for granulated pure metals or metal-compounds to be melted together, sometimes in vacuum or inert gas, and then a controlled set of cooling/holding/reheating steps are used to generate the final material. considering whether these syntheses could be practically decentralised, drexler's seminal paper (drexler ) considered the options and practicality issues associated with general-purpose synthesis of complex substances. since , the "engineering and physical sciences research council" (epsrc) have been funding a "dial-a-molecule" challenge which runs parallel to the work of others (crow , peplow , and commercial ventures such as "mattersift™" (manipulating matter at the molecular scale) have demonstrated the progress towards this goal. even where general-purpose synthesis capabilities are not available, the availability of knowledge does in principle allow relatively complex syntheses e.g. daraprim™, to be undertaken by small groups (hunjan ) . for j o u r n a l p r e -p r o o f inorganic materials, progress has been made with solar pyrometallurgy (neelameggham ) and although much development is needed, there would seem to be no fundamental reason why the required temperatures and composition constraints could not be achieved on small scale and with limited equipment. published proposals (crow , peplow ) have proposed that it is possible to build a standardised facility capable of carrying out an arbitrary sequence of unit operations required to make any organic compound. while the technologically maturity of decentralised synthesis of complex materials is lower than the decentralised production of complex components, many of the processes are actually feasible at present, and others are rapidly maturing.  finance: decentralised tokens of wealth (tokens of exchange) have existed for as long as societies have existed. in order for a token of exchange to continue to avoid the large exposure of current centralised financial systems, a token must retain the qualities of ubiquitous acceptance, transparent and irrevocable transactions; this is currently feasible. blockchain technology (swan ) has recently offered another decentralised system for secure and irrevocable transfer of wealth, allowing broad acceptance and thus meets the criteria for acceptability. blockchain-based currencies are however reliant on a communications system that is currently highly centralised, and so fall short of the security expected and exist in numbers of as-yet-incompatible forms. the difficulties with current blockchain technologies seem to be solvable, and this technology offers a promising approach to decentralised exchange of value. current, high-security banknotes and bullion fulfil many of the requirements for a decentralised approach to transactions, and do not incur the exposure that is inherent with blockchain-based currencies, but do incur a high risk of theft and the exposure of a physical transmission system if the transaction is to span significant distance. j o u r n a l p r e -p r o o f  communications: a communications system could be considered decentralised (within the population size envisaged) when it has no e value above zero, and is capable of communicating with any other (decentralised) population. secure encryption is currently possible (schneier ) , and despite some practical difficulties, mature approaches such as one-time-pads, seem to be proof against even projected (de wolf ) technologies. radio transmission on shortwave bands (using ionospheric reflection) of encrypted material can be received globally. assuming a mhz "open" band, and a very narrow bandwidth (and very slow transmission rate), many channels would be available in principle. this is a low level of practicality, but is must be noted that completely decentralised communication is inherently feasible. massively-redundant fibre-optic cable systems with decentralised routing systems are also technically feasible, and it is even feasible to consider significantly higher levels of design redundancy for undersea cables. while both feasible and practical for land-based systems, massive design redundancy appears to be feasible for undersea routes but not practical for the exposure level sought. selfdiscovering radio-based mesh communications for land-based systems are (author ) feasible at present and are likely to be more practical and economical than massively redundant fibre-optic systems for land-based communications. hybrid approaches, e.g. using self-discovering mesh for communications within a single land mass, and allowing access to a significant number of undersea cables, could meet the population levels and exposure levels to allow a claim of feasible decentralisation using current technology. suggests that fundamental breakthroughs may not be likely. so-called "ultracapacitor" technology (de rosa et al. ) may or may-not overtake battery storage for smaller power levels in the future. the decentralised production of biofuel using macro-algae (zev et al. , chen et al. ) is also immature, but the capability to treat sewage and create storable hydrocarbon fuel with high energy-density is promising and is perhaps the decentralised heating-energy storage mode that is closest to technical maturity at present. information. the information storage requirements for a community could include significant medical information, all data required for manufacture of complex components and synthesis of complex substances in addition to contractual, financial, genealogical etc. data. human-readable information storage (books, tablets) have very low exposure and high decentralisation currently. a decentralised and low-exposure approach for storage of machine readable information does j o u r n a l p r e -p r o o f however pose a non-trivial technological challenge. existing computer hard-disk drive storage technology is mature, but this approach has a very high technological exposure since the format of storage and the recovery of data is via a complex and proprietary system, and the actual storage medium is not user-accessible. a criterion of e < could in principle be achieved by massive redundancy, but in practice the use of identical operating systems and software make it likely that residual exposure will remain. technologies such as the d glass storage approach (kazansky et al. ) or proposals by the longnow foundation; or organisations such as "nanoarchival™ technology" avoid the reliance upon proprietary data retrieval systems and provide very long life -but still lack a mature and decentralised datawriting approach, and a mature and decentralised approach for reading stored data back into a machine-readable form. the advances needed in order to achieve a durable, low-exposure storage medium are immature but are technologically achievable. other: it is useful to note many other fields in which significant capabilities can be achieved with simple components: while far short of laboratory quality, the principles of spectrography and chromatography (lichtenegger et al. , ghobadian et al. are actually accessible at a domestic level, and microscope (prakash et al. ) (jones ) and mars explorer spacecraft. organisations such as the longnow corporation have considered the requirements for durable engineering, and plan items such as a " , year clock". in the context of this paper and earlier studies (author ), we can consider that it is practical to design at least some classes of components and equipment for a usable timeframe that is demonstrably longer than the time required to re-develop a production facility to recreate them; this criterion is a valid test of low exposure practicality. in summary: low exposure and decentralised options for a range of technologies have been examined: some are mature and some have a low level of technological maturity. it is likely that some could mature rapidly (e.g. additive/subtractive manufacturing, self-discovering communications networks, information storage), while others such as energy storage have absorbed enormous r&d effort already with limited progress. this does not mean that a trend to decentralisation cannot begin, simply that a decentralised society may have more sophisticated capabilities in some fields than others. the ability to form fixed-duration, ad-hoc associations to enable some largescale development are not only possible for a society comprising decentralised groups, but are considered to be essential. this conclusion differs from the assertion by jebari & jebari ( ) that "…isolated, self-sufficient, and continuously manned underground refuges…" are appropriate, rather proposing intentionally independent population units who control their specific interactions with other units, achieving reduced vulnerability but without forfeiting the capability to aggregate selected resources for mutual gain. smaller-scale concepts such a crowdsourcing approaches are already demonstrating somewhat similar options for shorter-duration, ad-hoc design advances. situations such as ships travelling in convoy are common and perhaps form a close analogy, demonstrating both the independence of each and the possibility of cooperation. this paper focussed on broad issues of technological vulnerability, but implementation details (resource usage efficiency, waste creation/treatment, gross greenhouse gas emissions and many other issues are also acknowledged. sociological/anthropological research (dunbar ) has indicated that quite small populations provide a sufficient sociological group size for most, and this conclusion seems to remain broadly valid even where high levels of electronic connection are possible (maccarron ). the concept of a technological system's exposure provides both a tool and a metric, which can be applied to either individuals or to populations of individuals, and can supply useful data to the forecasting process. population exposure is found to be high for many categories of current technological systems, and the current trend is to increased levels of population exposure. the categories that have been considered as typical, span and affect many goods and services that would be considered essential. items as diverse as internet usage and financial transactions already have multi-national levels of population exposure (and hence high levels of centralisation) and although various authors (diamond ) j o u r n a l p r e -p r o o f does not use the term "exposure" nor precisely describe the concept, he explains that environmental damage actually has a global exposure level. population exposure is a topic that does generate intuitive awareness of vulnerability: it can be observed that awareness of technological vulnerability exists at both national level (see j critical infrastructure protection, pub elsevier) and at individual level (slovic , martin , huddleston , kabel & chmidling , reiderer . since a measure of exposure correlates closely with the effort required to protect a system, a continued trend to centralisation and increased population exposure is very likely to lead to progressively herculean efforts to ensure that vulnerable loci are not attacked; such efforts are likely to include progressively wider surveillance to identify potential threats, and progressively stronger efforts to control and monitor access -each of which are themselves factors that can serve to make the service practically unavailable to individuals. if no value were attached to high and rising levels of population exposure, then highly centralised options are likely to continue to be preferred -but the consequences of the high and rising population exposure are demonstrated by reference to a metric of exposure, are also intuitively understood and are illustrated by the "continued centralisation" option in figure . if there were indeed no technological options for reducing the level of population exposure without major reductions in the levels of technological sophistication available, then large populations are indeed exposed to the danger of losing access to services. that scenario would indeed result in a catastrophic situation where a major reduction in sophistication of services occurs, but the remnant j o u r n a l p r e -p r o o f exposure is also reduced. that scenario has been labelled as the "apocalyptic survivor" scenario in figure . the third alternative shown in figure , is for progress towards a significantly decentralised society, with a comparatively low population exposure and a level of sophistication (in terms of technological services and goods available) that does not decrease and actually has the real possibility of advancing with time. in this paper, the description of "forecastable options" has been considered under each of the categories of high population exposure, and it has been noted that for each of them technological developments that enable significantly reduced population exposure exist. the current level of technological maturity of these options vary, but none are infeasible and complement the proposals advanced by a number of authors including gillies ( ) and blühdorn ( ) . j o u r n a l p r e -p r o o f in the course of considering decentralisation options, this paper has identified a small number of technological capabilities that would facilitate a more decentralised option, but which are currently at a low level of technological maturity. these include:  further advances on general purpose chemical synthesis  a durable, open-source machine-accessible information storage system that can be created and read in a decentralised context (requiring only minor development)  an self-discovering network using an open-source approach to allow information transmission (requiring some development)  a large-capacity, durable and economically accessible energy storage technology (requiring significant development)  further development of trustworthy and decentralised financial transaction systems (requiring some development).  a non-technological system to allow ad-hoc cooperation between decentralised groups, allowing resource aggregation without long-term centralisation (requiring significant development). despite the inevitable variations in technological maturity across a broad range of technologies, the analyses have concluded firstly that centralisation and high population exposure result in severe and increasing vulnerabilities for large numbers of persons, and secondly that the combination of maturing decentralised technological capabilities and the storage of knowledge allows a transition to a "sophisticated decentralisation" model to be considered as a serious option. while not the primary topic of this paper, it is noted that even in the presence of technological options, change may not occur until some triggering event occurs; events that could trigger a more rapid transition to a "sophisticated decentralisation" could j o u r n a l p r e -p r o o f include a truly major and long-term disruption of some highly centralised technology such as undersea cables or an irremediable malfunction of international financial systems, or a pandemic requiring high levels of population isolation . the analysis of technological exposure and reduced exposure options have concluded that practical options for substantial decentralisation exist, or could be reasonably forecast as possible. it has also been proposed that there are substantive and immediate reasons to consider a qualitatively distinct "fork" from the high population exposure of current centralised society to a more decentralised model. any selection of a decentralised technological model might be triggered by some event which crystallised the exposure of a highly centralised model: the drivers that had produced the centralised model will still remain however, and will arguably tend to cause a re-centralisation without ongoing efforts. this issue is outside the scope of this paper, but is noted as a topic requiring further research. the capability for decentralised and machine-accessible storage of knowledge and the creation of complex components and substances has recently, or will soon, create a cusp at which local equipment is capable of reproducing itself. sufficient computation facilities at local scale are already able to make genuine advances, and with equipment capable of replication, is sufficient to allow fully sustainable, sophisticated and decentralised communities to diverge from current trends. declarations of interest: none consumer preferences for household-level battery energy storage on some recent definitions and analysis frameworks for risk, vulnerability, and resilience d printing technique applied to rapid casting confronting future catastrophic threats to humanity dark ages ii: when the digital data die eco-political hopes beyond sustainability. global discourse existential risks: analyzing human extinction scenarios and related hazards calling dunbar's numbers colombian ancillary services and international connections: current weaknesses and policy challenges digital vellum macroalgae for biofuels production: progress and perspectives undersea cables and the future of submarine competition addressing the harm of total surveillance: a reply to professor neil richards mechanics of turn-milling operations the anything factory sustainable growth-an impossibility theorem the knowledge: how to rebuild civilization in the aftermath of a cataclysm black code: censorship, surveillance, and the militarisation of cyberspace collapse: how societies choose to fail or succeed cascading blackout overall structure and some implications for sampling and mitigation molecular engineering: an approach to the development of general capabilities for molecular manipulation how many friends does one person need?: dunbar's number and other evolutionary quirks intel's management engine is a security hazard, and users need a way to disable it hype and heavy tails: a closer look at data breaches how to hack a turned off computer, or running unsigned code in intel management engine the protocols kinematic self-replicating machines an innovative homemade instrument for the determination of doxylamine succinate based on the electrochemiluminescence of ru(bpy) + paul mason's postcapitalism emerging technologies, catastrophic risks, and ethics: three strategies for reducing risk a critical review of cascading failure analysis and modelling of power system in: near-net shape manufacturing of miniature spur gears by wire spark erosion machining. materials forming, machining and tribology leontief based model of risk in complex interconnected infrastructures weaving the web: otlet's visualizations of a global information society and his concept of a universal civilization long-lost satellite tech is so old nasa can't read it. tech & science. nasa image. observer. nasa satellite lost for years recovered by amateur astronomer when do states disconnect their digital networks? regime responses to the political uses of social media. the communication review conceptual design and dimensional synthesis for a -dof module of 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ex vivo imaging longnow foundation total surveillance, big data, and predictive crime technology: privacy's perfect storm is your algorithm dangerous? solar pyrometallurgy-an historic review electronic payment systems. artech house organic synthesis: the robo-chemist. the race is on to build a machine that can synthesize any organic compound. it could transform chemistry permanent archival solution: nanoarchival provides ultra-long term archival solutions to enterprise customers, based on its proprietary a dangerous trend of cybercrime: ransomware growing challenge population dynamics with and without selection optical microscope d printing based on imaging data: review of medical applications doomsday goes mainstream high performance spiro ammonium electrolyte for electric double layer capacitors emerging threats: outer space, cyberspace, and undersea cables von neumann machine. encyclopedia of computer science. th. pages - monsters in cyberspace cyberphobia and cultural panic in the information age. information applied cryptography, second edition: protocols, algorthms, and source code in c, th anniversary edition isbn information. online isbn: . print isbn a new rationale for returning to the moon? protecting civilization with a sanctuary a thesis submitted to faculty of graduate studies and research, mcgill university in partial fulfilment of the requirements of the degree of the perception of risk energy and civilization; a history hulking transformers prove a challenge for vulnerable grid. e&e - - and see energy news digest for blockchain: blueprint for a new economy censorship and surveillance in the digital age: the technological challenges for academics the designer's guide to disk drives the potential impact of quantum computers on society. ethics and information technology high-yield bio-oil production from macroalgae (saccharina japonica) in supercritical ethanol and its combustion behaviour key: cord- -oqiwnjpp authors: cainzos-achirica, miguel; bilal, usama title: polypill for population-level primary cardiovascular prevention in underserved populations at heterogeneous risk — a social epidemiology counterargument date: - - journal: am j med doi: . /j.amjmed. . . sha: doc_id: cord_uid: oqiwnjpp nan use of polypills combining multiple pharmacotherapies for cardiovascular disease prevention is a hot topic in cardiovascular medicine. in a low-resource, mostly black community in alabama with average % -year cardiovascular disease risk, a pill combining a statin plus three blood pressure-lowering medications improved adherence and control of proximal risk factors. in iran, a combination of aspirin, a statin and two anti-hypertensive drugs reduced cardiovascular disease events in a mixed primary/secondary prevention population including % individuals with established cardiovascular disease and % with diabetes, as compared to a "minimal care" intervention. these findings have re-sparked interest in scaling-up the use of polypills for cardiovascular prevention, from individual high-risk patients to entire populations at heterogeneous risk-the so-called polypill paradigm for population-level cardiovascular disease prevention. , this was first proposed by wald and law in , who projected that a pill combining six drugs could reduce the incidence of cardiovascular disease up to % in the uk. multiple concerns were subsequently raised including ethics issues, medicalization of prevention, potential for overtreatment of mostly low-risk individuals, pharmacological side effects, and costs. a few years later, bittencourt and colleagues demonstrated that implementation of the inclusion criteria of initial polypill population-level trials would define target populations comprising a majority of individuals unlikely to derive benefit. more recently, this paradigm has evolved to focus on "underserved populations", i.e., low-resource communities with poor access to healthcare which typically face higher rates of cardiovascular disease than those with more resources. the assumption is that treating the entire population of underserved communities with polypills could markedly curtail their rates of cardiovascular disease, potentially reducing disparities. this has been followed by a call for additional trials comparing population-level polypill-based interventions to more "precise" approaches. , in our opinion, use of pills combining various pharmacotherapies represents a promising approach with enormous potential to improve adherence and clinical outcomes in patients who require such medications. on the other hand, although we welcome any efforts aimed at improving the cardiovascular health of low-resource communities through interventions with the potential to improve equity, important conceptual issues arise when evaluating a population-level polypill paradigm for cardiovascular disease prevention. importantly, although this approach is often confronted by precision medicine as its most intuitive counterargument, we pose that a social epidemiology perspective should also be brought into the conversation to fully characterize its strengths and weaknesses. first, how would such an intervention be funded? implementation would involve not only the production and distribution of millions of chronic polypills, but also the development of a complex infrastructure aimed at ensuring trial-like long-term adherence in communities where poor adherence has traditionally represented a key barrier. would current societal arrangements allowing communities to remain underserved in countries such as the u.s. be willing to fund such a costly intervention? ensuring the necessary surveillance and treatment of pharmacological side effects would also prove challenging. our second concern relates to the conflation of polypill-based prevention interventions with geoffrey rose's "population-level" strategy. , , in his landmark "strategy of preventive medicine", rose defined this as interventions aimed at reducing the incidence of disease in entire populations by addressing the fundamental factors (mass influences, typically cultural and socioeconomic determinants) that cause some populations to have higher rates of disease than others. rose's "population-level" interventions would not include scaled-up versions of highrisk individual approaches (such as the polypill), since these fail to address fundamental factors, but rather, proximal ones-for example, high cholesterol levels. rose did not dismiss individuallevel approaches, but rather emphasized that their main benefit is on treating higher-risk individuals in whom the benefits outweigh the risks. on the other hand, from a population standpoint, the high-risk approach is akin to famine relief, which feeds the hungry in the short term but does not tackle the underlying causes, which persist: "success is only palliative and temporary". third, in tackling the high burden of cardiovascular disease in underserved populations, there is indeed a need to consider the underlying fundamental causes and their connection with other adverse health outcomes that disproportionately affect individuals of low socioeconomic status, as this may be crucial to identify the most impactful and cost-effective interventions ( figure) . the association between poverty and these outcomes occurs through a variety of pathways and ultimately yields a markedly reduced quality of life and life expectancy. consequently, ignoring fundamental causes and focusing on proximal factors may allow those fundamental causes to continue affecting health through other mechanisms. more radical, upstream approaches are likely to have a larger impact in the health of those communities. another conceptual concern relates to the frequent comparison of the nature and potential benefits of a polypill approach with those of vaccines. in the absence of socioeconomic interventions that can prevent the occurrence of some viral outbreaks, such as the recent coronavirus pandemic, widespread vaccination becomes crucial to reduce the contagion of vulnerable persons through individual and, especially, herd immunity. conversely, cardiovascular disease has well-established proximal risk factors and upwards determinants, most of which are addressable. moreover, polypills would provide only limited individual "immunity", and no herd protection. we humbly believe that avoidance of this analogy would help prevent misconceptions. from a research standpoint, there have been calls for further trials as means to characterize the potential benefits of the polypill approach even further. , importantly, the control arm of a randomized trial should mimic the best currently existing intervention. according to the united nations, "everyone has the right to a standard of living adequate for the health and well-being of himself and of his family, including food, clothing, housing and medical care and necessary social services". in a recent trial in rural pakistan, access to high-quality public healthcare curtailed mortality by more than % in just months. with these recommendations and evidence already available, any future randomized trial of polypill in underserved communities in which at least one of the study arms does not include optimal access to healthcare-i.e., tackles the status of "underserved"-would seem ethically questionable. but, do we need more trials in underserved communities? access to care is already known to have indisputable, broad health benefits. more generally, interventions aimed at improving basic life conditions are tremendously powerful. for most, it would seem counterintuitive to fund a trial comparing water sanitation to an intervention based on the widespread use of chronic preventive antibiotic therapy. or, as rose put it: " [the high risk strategy] is analogous to vaccinating a population against cholera rather than improving their water supply". an argument in favor of the use of polypills builds on the low feasibility of interventions tackling the status of underserved. for the same reason, should we devote millions of dollars to evaluate/implement large-scale pharmacological-based prevention approaches, or should those resources be invested in improving basic life conditions and access to care among underserved areas? the latter would likely reduce the incidence and case-fatality rates not only of cardiovascular disease, but also of many other conditions in those communities. finally, we pose that discussions of interventions with the potential to affect very large populations should be enriched with additional perspectives, including ethics, social values and priorities, and feasibility considerations. civic society leaders, patient representatives, medical humanists, health systems managers and even philosophers should be involved for further context and reflection. albeit crucial, data alone falls short capturing the variety of considerations that need to be leveraged when building healthier and better societies. more importantly, we already have plenty of data demonstrating the benefits of improved life conditions and more equitable healthcare; we just need the will to implement them. abbreviations: ascvd = atherosclerotic cardiovascular disease; cvd = cardiovascular disease; ncds = non-communicable diseases; std = sexually transmitted diseases polypill for cardiovascular disease prevention in an underserved population effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (polyiran): a pragmatic, clusterrandomised trial the new york times. this daily pill cut heart attacks by half. why isn't everyone getting it? available online at the polypill revisited: why we still need population-based approaches in the precision medicine era a strategy to reduce cardiovascular disease by more than % polypill therapy, subclinical atherosclerosis, and cardiovascular events-implications for the use of preventive pharmacotherapy: mesa (multi-ethnic study of atherosclerosis) cardiovascular disease prevention at a crossroads: precision medicine or polypill? the strategy of preventive medicine commentary: what is a population-based intervention? returning to geoffrey rose a community-based intervention for managing hypertension in rural south asia